Isothiazole derivatives as pim kinase inhibitors and preparation methods and use in medicinal manufacture thereof

ABSTRACT

PIM kinase inhibitor compound having a structure as represented by Formula I, and isomers, diastereomers, enantiomers, tautomers, and pharmaceutically acceptable salts thereof. The compounds significantly inhibit the Pim kinase activity and are used to prepare drugs to treat PIM kinase mediated diseases, such as cancers, multi drug resistance, and inflammatory bowel disease. Also provided are methods for preparing and using the compounds represented by Formula I.

CROSS-REFERENCE AND RELATED APPLICATIONS

The subject application is a continuation-in-part of U.S. patentapplication Ser. No. 14/177,156 filed on Feb. 10, 2014, now allowed,which is a continuation of PCT international applicationPCT/CN2012/001060 filed on Aug. 8, 2012, which in turn claims priorityon Chinese patent applications CN 201110229731.X filed on Aug. 11, 2011and CN 201210271738.2 filed on Aug. 1, 2012. The contents and subjectmatters of all the priority applications are incorporated herein byreference.

TECHNICAL FIELD

The present invention relates to medicinal chemistry, particularly, PIMkinase inhibitors, methods of preparation, and their pharmaceuticalapplication in treating diseases.

BACKGROUND

PIM kinase family consists of three homologous serine/threonine kinases,Pim-1, Pim-2, and Pim-3, which belongs to calmodulin-dependent proteinkinase-related family (CAMK). Researchers have shown that PIM kinasesare widely expressed in hematopoietic tissues (J. Biol. Chem., 280,14168-14176, 2005; Blood, 105, 4477-4483, 2005) and play important rolesin cell survival and proliferation. Since PIM kinases are overexpressedin a variety of malignancies and inflammations (J. Exp. Med., 201,259-266, 2005; Biochem. Soc. Trans., 32, 315-319, 2004), they are moreand more being targeted for treating cancers and immune dysfunctions.PIM-1 (Provirus Integration of Maloney 1) is originally identified in aseries of insertional mutagenesis studies of retroviruses, as a frequentproviral integration site in Moloney murine leukemia virus-inducedT-cell lymphomas, and PIM-1 is named based on that finding (Cell, 37,141-150, 1984). It is found later that the genes encoding PIM-2(Provirus Integration of Maloney 2) have the same defect (J. Clin.Invest., 115, 2679-2688, 2005). Pim-2 has similar effects as andcompensatory to Pim-1 (J EMBO, 14, 2536, 1995). PIM-3 is initially namedas KID-1 (Kinase Induced by Depolarization 1), but renamed to Pim-3because of its high sequence similarity to Pim-1 (Nature, 428, 332-337,2005; Cell, 56, 673-682, 1989). PIM-1, 2, 3 are overly expressed in manyhematopoietic malignancies (Proc. Natl. Acad. Sci. U.S.A., 86,8857-8861, 1989). PIM-1 is found to be overexpressed in the developmentof prostate cancer (J. Clin. Pathol., 59, 285-288, 2006). PIM-2expression is elevated in human chronic lymphocytic leukemia andnon-Hodgkin's lymphoma leukemia (Leuk. Lymph., 45, 951-955, 2004), theaberrant expression of PIM-3 is believed to have played an importantrole in the development and proliferation of liver fibroma (Int. J.Cancer, 114, 209-218, 2005) and pancreatic cancer (Cancer Res., 66,6741-6747, 2006).

PIM-1, PIM-2, and PIM-3 have effects on the survival and proliferationof hematopoietic cells in response to growth factors stimulation. PIM-1,2, 3 triple knockout mice are viable and fertile while displayingreduced body size and impairment of proliferation of hematopoietic cellsin response to growth factors. Knocking out one of 3 kinases does nothave obvious effect on mice, indicating some overlapping functions amongPIM kinases (Cell, 56, 673-682, 1989). The substrates of PIM kinasesinclude Bc1-2 family members such as pro-apoptotic BAD protein (FEBSLetters, 571, 43-49, 2004), cell cycle regulating p21 (Biochem. Biophys.Acta, 1593, 45-55, 2002), CDC25A, C-TA (J. Biol. Chem., 279,48319-48328, 2004), protein synthesis related 4EBP1 (Blood, 105,4477-4483, 2005). These functions of PIM kinases indicate that PIMkinases can prevent apoptosis and promote cell growth and proliferation.Their overexpression in cancer cells promotes the survival andproliferation of the cancer cells. Therefore, inhibiting the PIM kinaseactivities in cancer cell is a new effective way of treating cancers.

Based on the evidence that PIM kinases are involved in hematologicalcancers and solid tumors, a number of PIM inhibitors have been developedto treat a variety of cancers. It is shown in a series of cellularassays and in vivo models that PIM inhibitors can significantly inhibitAcute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML),Chronic myelogenous leukemia (CML), Non-Hodgkin's Lymphoma (NHL), andMultiple Myeloma (MM) cell proliferation and tumor growth in xenograftmodel (Clin. Cancer Res. 20(7), 1834-1845, 2014; Blood 123(6), 905-913,2014; Blood 122(21), 4435, 2013). It has also been demonstrated that PIMinhibitors are useful to treat PIM overexpressed solid tumors such aspancreatic cancers (Cancer Biol. Ther. 7(9), 1352-9, 2008 Cancer Res.2006; 66(13):6741-7; Cancer Res. 70(24), 10288-10298, 2010), prostatecancers (Prostate, 65(3), 276-86, 2005; Prostate, 73(13), 1462-1469,2013), liver cancers (J. Surg. Res., 153(1), 17-22, 2009; Int. J.Cancer, 114(2), 209-18, 2005), gastric cancer (J. Cancer Res. Clin.Oncol., 134(4), 481-8, 2008), and bladder cancer (J. Exp. Clin. CancerRes., 29, 161, 2010).

Moreover, resistance to chemotherapeutics and molecularly targeted drugsis a major obstacle in cancer treatment (Drug Resistance Updat. 12,114-126. 2009). It has also been reported that PIM kinases are involvedin the expression and activity of MDR-1 and BCRP, two of the mostimportant drug efflux transporters. “It is abundantly clear from thepreclinical models that PIM inhibition can significantly reverse drugresistant phenotypes.” See Drug Resistance Updates, 14, 203-211, 2011.It has been demonstrated that the use of PIM inhibitors in combinationwith chemotherapeutics can significantly increase their potenciesagainst drug resistant prostate cancer (Mol. Cancer Ther. 8, 2882-2893,2009). Therefore, PIM kinase inhibitors are used to reverse the multidrug resistance.

Further, PIM kinases are expressed following T cell activation. Studiesshow that therapeutic dosing of a PIM-1/3 inhibitor is efficacious in aCD4+ T cell-mediated model of inflammatory bowel disease. Oraladministration of AR452530 significantly decreases colon inflammation,gland loss, edema, and mucosal thickness by at least 80%. Therefore,PIM-1/3 kinases have an important role in CD4+ T cell responses andinhibition of this activity may provide a therapeutic benefit in Tcell-mediated diseases. See Cellular Immunology, 272, 200-213, 2012.

SUMMARY OF THE INVENTION

The present invention provides chemical compounds having certainbiological activities that include, but not limited to, inhibiting cellproliferation, promoting apoptosis, and modulating protein kinaseactivities. The present invention provides compounds that inhibit theactivities of PIM-1, PIM-2 and PIM-3 kinases. The present invention alsoprovides methods for preparing the novel chemical compounds and analogsthereof, and methods of using these compounds to treat cancers,autoimmune diseases, allergic reactions, and organ transplant rejection.

The PIM kinase inhibitors of the present invention have the followinggeneral structural Formula I, and their stereoisomers, tautomers, andpharmaceutically acceptable salts,

wherein Z₁ and Z₂ are independently selected from a CR₂, a CR₃, and anitrogen (N), provided that Z₁ and Z₂ cannot be N at the same time;

R₁ is a hydrogen (H), —NHR₄, a halogen, a hydroxyl, an alkyl, a cyano,or a nitro group;

R₂ and R₃ are each independently selected from a hydrogen, —NHR₅, ahalogen, a hydroxyl, a substituted or unsubstituted alkyl, an alkenyl,an alkynyl, an alkoxyl, a cycloalkyl, an amino, a cyano, and a nitrogroup;

R₄ is a hydrogen, —C(═O)—R₅, a substituted or unsubstituted alkyl, acycloalkyl, a heterocyclyl, an aryl, or a heteroaryl;

R₅ is a substituted or unsubstituted alkyl, an alkenyl, an alkynyl, analkoxyl, a cycloalkyl, an amino, or a substituted amino group;

R₆ is a substituted or unsubstituted aryl, a heteroaryl, a cycloalkyl,where each substituted R₆ group is substituted with up to foursubstituents that is a halogen, a cyano, an amino, a C₁₋₄ alkyl, a C₃₋₆cycloalkyl, an alkoxyl, a nitro, a carboxy, a carbonyl, a carboalkoxy,or an aminocarboxy;

E is an OR₂₂, a SR₂₂, or a SO₂R₂₂; R₂₂ is an optionally substitutedC₁-C₈ hydrocarbon group or a group described in the following formula:

wherein each of R₂₃, R₂₄, R₂₅ is independently selected from a H, ahalogen, an OR₁₅, a NR₁₆R₁₇, a C(═O)NR₁₈R₁₉, or an optionallysubstituted C₁-C₈ hydrocarbon group; or R₂₃, R₂₄ and R₂₅, together withthe atoms to which they are attached, may be joined together to form achain so that the ring to which they are attached is a substitutedC₆-C₁₄ membered spiral ring, a bicyclic ring, or a fused ring group;

G₁ is —CH or N;

G₂ is NR₂₈, CHR₂₉ or O;

B1 and B2 each independently represents 0, 1, 2, or 3;

B3 is 0, 1, or 2;

B4 is 0 or 1;

Each of R₁₆, R₁₇, R₁₈, R₁₉, R₂₆ and R₂₇ is independently selected from aH or an optionally substituted C₁-C₈ hydrocarbon group;

R₂₈ is H, an optionally substituted hydrocarbon group, an optionallysubstituted cyclic hydrocarbon group, an optionally substitutedheterocyclic hydrocarbon group, a C(═O)R₃₀, C(═O)OR₃₀, or a C(═O)NHR₃₀;

R₂₉ is an OH, a NHR₃₀, a C(═O)OR₃₀, or a C(═O)NHR₃₀; and

R₃₀ is H or an optionally substituted C₁-C₈ hydrocarbon group.

In some embodiments of the present invention, the compounds of Formula Ior a stereoisomer, tautomer, or pharmaceutically acceptable salt thereofhave Z₁ and Z₂ that are CR₂ and CR₃, respectively.

In some other embodiments of the present invention, the compounds ofFormula I or a stereoisomer, tautomer, or pharmaceutically acceptablesalt thereof have R₂ and R₃ that are independently selected from ahydrogen, a methyl, an ethyl, a halogen, and a cyano group.

In yet another embodiments of the present invention, in the compounds ofFormula I and their stereoisomer, tautomer, or pharmaceuticallyacceptable salt thereof, Z₁ is CR₂, Z₂ is CR₃, and E is O—R₂₂, so thatthey have the following structure of formula II:

DETAILED DESCRIPTION OF THE INVENTION

The PIM kinase inhibitors of the present invention and theirstereoisomers, tautomers, and pharmaceutically acceptable salts have thefollowing general structural Formula I:

wherein Z₁ and Z₂ are independently selected from a CR₂, a CR₃, and anitrogen (N), provided that Z₁ and Z₂ cannot be N at the same time;

R₁ is a hydrogen (H), —NHR₄, a halogen, a hydroxyl, an alkyl, a cyano,or a nitro group;

R₂ and R₃ are each independently selected from a hydrogen, —NHR₅, ahalogen, a hydroxyl, a substituted or unsubstituted alkyl, an alkenyl,an alkynyl, an alkoxyl, a cycloalkyl, an amino, a cyano, and a nitrogroup;

R₄ is a hydrogen, —C(═O)—R₅, a substituted or unsubstituted alkyl, acycloalkyl, a heterocyclyl, an aryl, or a heteroaryl;

R₅ is a substituted or unsubstituted alkyl, an alkenyl, an alkynyl, analkoxyl, a cycloalkyl, an amino, or a substituted amino group;

R₆ is a substituted or unsubstituted aryl, a heteroaryl, a cycloalkyl,where each substituted R₆ group may be substituted with up to foursubstituents that is a halogen, a cyano, an amino, a C₁₋₄ alkyl, a C₃₋₆cycloalkyl, an alkoxyl, a nitro, a carboxy, a carbonyl, a carboalkoxy,or an aminocarboxy;

E is an OR₂₂, a SR₂₂, or a SO₂R₂₂; R₂₂ is an optionally substitutedC₁-C₈ hydrocarbon group or a group described in the following formula:

wherein each of R₂₃, R₂₄, R₂₅ is independently selected from a H, ahalogen, an OR₁₅, a NR₁₆R₁₇, a C(═O)NR₁₈R₁₉, or an optionallysubstituted C₁-C₈ hydrocarbon group; or R₂₃, R₂₄ and R₂₅, together withthe atoms to which they are attached, may be joined together to form achain so that the ring to which they are attached is a substitutedC₆-C₁₄ membered spiral ring, a bicyclic ring, or a fused ring group;

G₁ is —CH or N;

G₂ is NR₂₈, CHR₂₉ or O;

B1 and B2 each independently represents 0, 1, 2, or 3;

B3 is 0, 1, or 2;

B4 is 0 or 1;

Each of R₁₆, R₁₇, R₁₈, R₁₉, R₂₆ and R₂₇ is independently selected from ahydrogen (H) or an optionally substituted C₁-C₈ hydrocarbon group;

R₂₈ is H, an optionally substituted hydrocarbon group, an optionallysubstituted cyclic hydrocarbon group, an optionally substitutedheterocyclic hydrocarbon group, a C(═O)R₃₀, C(═O)OR₃₀, or a C(═O)NHR₃₀;

R₂₉ is an OH, a NHR₃₀, a C(═O)OR₃₀, or a C(═O)NHR₃₀; and

R₃₀ is H or an optionally substituted C₁-C₈ hydrocarbon group.

In some embodiments of the present invention, the compounds of Formula Ior a stereoisomer, tautomer, or pharmaceutically acceptable salt thereofhave Z₁ and Z₂ that are CR₂ and CR₃, respectively.

In some other embodiments of the present invention, the compounds ofFormula I or a stereoisomer, tautomer, or pharmaceutically acceptablesalt thereof have R₂ and R₃ that are independently selected from ahydrogen, a methyl, an ethyl, a halogen, and a cyano group.

In yet another embodiments of the present invention, the compounds ofFormula I and their stereoisomer, tautomer, or pharmaceuticallyacceptable salt thereof have the structure of formula I where Z₁ is CR₂,Z₂ is CR₃, and E is O—R₂₂, and the structure is described as thefollowing formula II:

In some embodiments of the present invention, the compounds of Formula Ior II, or a stereoisomer, tautomer, or pharmaceutically acceptable saltthereof are provided where R₁ is a hydrogen, an amino or a fluoro.Preferred embodiments of the compounds of Formula II of the presentinvention are provided at the following Table I.

In some embodiments of the present invention, the compounds of Formula Ior II, or a stereoisomer, tautomer, or pharmaceutically acceptable saltthereof are provided where R₆ is a substituted or unsubstituted aryl, ahetero aryl, a C₄-C₆ cycloalkyl, a partially unsaturated C₄-C₆cycloalkyl, where each group can be substituted with up to foursubstituents that is a halogen, a cyano, an amino, an alkyl, an alkoxy,a cycloalkyl, a nitro, a carboxyl, a carboalkoxy, an aminocarboxy, asubstituted aminocarbonyl, an aminosulfonyl, a substitutedaminosulfonyl, or an alkoxyalkyl.

In some embodiments of the present invention, the compounds of Formula Ior II, or a stereoisomer, tautomer, or pharmaceutically acceptable saltthereof are provided where R₆ is a substituted or unsubstituted phenyl,where the phenyl group can be substituted with up to three substituentsthat is a hydrogen, a cyano, a nitro, a halogen, a hydroxyl, an amino,an alkoxy, a substituted amino, an alkyl, a cycloalkyl. In someembodiments of the present invention, the compounds of Formula I or IIor a stereoisomer, tautomer, or pharmaceutically acceptable salt thereofare provided where R₆ is 2,6-difluorophenyl.

In some embodiments of the present invention, the compounds of Formula Ior II, or a stereoisomer, tautomer, or pharmaceutically acceptable saltthereof are provided where R₂ and R₃ are each independently selectedfrom a hydrogen, a halogen, a cyano, a methyl, or an ethyl.

In some embodiments of the present invention, the compounds of Formula Ior II, or a stereoisomer, tautomer, or pharmaceutically acceptable saltthereof are provided where R₂₂ is a substituted or unsubstitutedcyclobutyl, a cyclopentyl, a cyclohexyl, a cycloheptyl, an azetidyl, apyrrolindyl, a pyridyl, an azepanyl, an oxetyl, a tetrahydrofuryl, atetrahydropyranyl, where the R₂₂ group may be substituted with up tothree substitutents that is an amino, a hydroxy, a methyl, an ethyl, ora methoxy; R₁ is a hydrogen, an amino, or a fluoro; R₂ and R₃ are eachindependently selected from a hydrogen, a halogen, and a methyl; R₆ is asubstituted or unsubstituted phenyl, where the phenyl group can besubstituted with up to three substituents that is a hydrogen, a cyano, anitro, a halogen, a hydroxyl, an amino, an alkoxy, a substituted amino,an alkyl, or a cycloalkyl.

In some embodiments of the present invention, the compounds of Formula Ior II, or a stereoisomer, tautomer, or pharmaceutically acceptable saltthereof are provided where R₂₂ is a substituted or unsubstitutedcyclobutylmethyl, a cyclopentylmethyl, a cyclohexylmethyl, acycloheptylmethyl, an azetidylmethyl, a pyrrolindylmethyl, apyridylmethyl, an azepanylmethyl, an oxetylmethyl, atetrahydrofurylmethyl, a tetrahydropyranylmethyl, where the R₂₂ groupmay be substituted with up to three substitutents that is an amino, ahydroxy, a methyl, an ethyl, or a methoxy; R₁ is a hydrogen or an amino;R₂ and R₃ are each independently selected from a hydrogen, a halogen,and a methyl; R₆ is a substituted or unsubstituted phenyl, where thephenyl group can be substituted with up to three substituents that is ahydrogen, a cyano, a nitro, a halogen, a hydroxyl, an amino, an alkoxy,a substituted amino, an alkyl, or a cycloalkyl.

A preferred embodiment of the present inventions is a compound ofFormula II, where R₂₂ is a substituted or unsubstituted cyclohexyl,azetidyl, pyrrolindyl, pyridyl, azepanyl, tetrahydrofuryl, ortetrahydropyranyl group, and preferably a cyclohexyl, pyrrolindyl,pyridyl, or azepanyl group, where the R₂₂ group may be substituted withup to three substitutents that is an amino, a hydroxy, a methyl, anethyl, or a methoxy group, and preferably an amino, a hydroxy, or amethyl group; R₁ is a hydrogen, an amino, or a fluoro; R₂ and R₃ areeach independently selected from a hydrogen, a halogen, and a methyl,and preferably R₂ is a hydrogen and R₃ is a halogen; R₆ is a substitutedor unsubstituted phenyl, where the phenyl group can be substituted withup to three substituents that is a hydrogen, a cyano, a nitro, ahalogen, a hydroxyl, an amino, an alkoxy, a substituted amino, an alkyl,or a cycloalkyl, and preferably a hydrogen, a cyano, or a halogen, andmost preferably a hydrogen or a halogen.

Yet another preferred embodiment of the present inventions is a compoundof Formula II, where R₂₂ is a substituted or unsubstitutedcyclohexylmethyl, azetidylmethyl, pyrrolindylmethyl, pyridylmethyl,azepanylmethyl, tetrahydrofurylmethyl, or tetrahydropyranylmethyl group,and preferably, a cyclohexylmethyl, pyrrolindylmethyl, pyridylmethyl, orazepanylmethyl group, where the R₂₂ group may be substituted with up tothree substitutents that is an amino, hydroxy, methyl, ethyl, ormethoxy, and preferable an amino, hydroxy, or methyl; R₁ is a hydrogen,an amino, or a fluoro; R₂ and R₃ are each independently selected from ahydrogen, a halogen, and methyl, and preferably R₂ is a hydrogen and R₃is a halogen; R₆ is a substituted or unsubstituted phenyl, where thephenyl group can be substituted with up to three substituents that is ahydrogen, a cyano, a nitro, halogen, hydroxyl, an amino, an alkoxy, asubstituted amino, an alkyl, or a cycloalkyl, and preferably a hydrogen,a cyano, or a halogen, and most preferably a hydrogen or a halogen.

Yet another preferred embodiment of the present inventions is a compoundof Formula II, wherein R₂₂ is a substituted C₂-C₅ alkyl, the substitutedR₂₂ group may be substituted at any position on the substituent with upto four substitutents that is an amino, an alkylamino, a hydroxy, ahalogen, a methyl, an ethyl, a halogenated methyl, or a helogenatedethyl group; R₁ is a hydrogen, an amino, or a fluoro; R₂ is a hydrogen;R₃ is, a halol; and R₆ is a substituted or unsubstituted phenyl, and thesubstituted phenyl group is substituted with up to three substituentsthat is a hydrogen, a methyl, or a halogen.

As used herein, the term ‘substituent’ refers to atom or atomic groupthat replaces the hydrogen atoms of the molecule. As used herein,‘optionally substituted’ substituent refers to substituents that each ofthe replaceable hydrogen atoms on the substituents may be substituted byother atom or atomic group.

As used herein, the term ‘hydrocarbon group’ refers to alkyl group(saturated aliphatic group), alkenyl group (having at least onecarbon-carbon double bond), alkynyl group (having at least onecarbon-carbon triple bond); the ‘hydrocarbon group’ may be linear,branced or cyclic; the ‘hydrocarbon group’ may be aliphatic or aromatic.

As used herein, the term ‘cyclic hydrocarbon group’ refers to cycloalkylgroup or cycloalkenyl group (having at least one carbon-carbon doublebond), aromatic group; ‘cyclic hydrocarbon group’ may be monocyclic,bicyclic or multi-cyclic group; ‘cyclic hydrocarbon group’ may be spiralor fused ring.

As used herein, the term ‘hetero cyclic hydrocarbon group’ refers tocycloalkyl group or cycloalkenyl group (having at least onecarbon-carbon double bond), aromatic group with one or more ring atomsare hetero atoms such as N, O, S, or combination thereof; ‘hetero cyclichydrocarbon group’ may be monocyclic, bicyclic or multi-cyclic group;‘hetero cyclic hydrocarbon group’ may be spiral or fused ring.

As used herein, the term ‘substituent’ include but not limited to:halogen (F, Cl, Br, I), —OR₂₆, —OC(═O) R₂₆, —OC(═O)NR₂₆R₂₇, ═O, —SR₂₆,—SOR₂₆, —SO₂R₂₆,—SO₂NR₂₆R₂₇, —C(═O)R₂₆, —C(═O)OR₂₆, —C(═O)NR₂₆R₂₇,—R₂₆CN, —NR₂₆R₂₇, —NHC(═O)R₂₆, —NHC(═O)NR₂₆R₂₇, —NHC(═S)NR₂₆R₂₇,halogenated (F, Cl, Br, I) hydrocarbon; and each of R₂₆ and R₂₇ isindependently selected from H or optionally substituted C₁-C₈hydrocarbon group.

The compounds described in the present invention that are acidic innature can form pharmaceutically acceptable salts by reacting withphysiologically compatible organic or inorganic bases, such as readilysoluble alkali and alkaline earth salts, and salts formed from reactingwith ammonia, N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine,lysine, ethanolamine, glucosamine, sarcosine, serine,tris(hydroxymethyl)aminomethane, 1-amino-2,3,4-butanetriol.

The compounds described in the present invention that are basic innature can form pharmaceutically acceptable salts by reacting withphysiologically compatible organic or inorganic acids, such as the saltsformed by reacting with hydrochloric acid, hydrobromic acid, sulfuricacid, phosphoric acid, methanesulfonic acid, toluene-sulfonic acid,carbonic acid, succinic acid, citric acid, benzoic acid, oxalic acid,malonic acid, salicylic acid, malic acid, fumaric acid, maleic acid,acetic acid, ascorbic acid.

The compounds in the present invention may be pure chiral compounds,racemic mixtures, optically active compounds, pure diastereomers, ormixed diastereomers.

The present invention provides PIM kinase inhibitors which include thefollowing compounds:6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-4-ylmethoxy)isothiazol-4-yl)picolinamide,N-(5-(azetidin-3-ylmethoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-4-yloxy)isothiazol-4-yl)picolinamide,6-(2,6-difluorophenyl)-5-fluoro-N-(5-(pyrrolidin-3-yloxy)isothiazol-4-yl)picolinamide,6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-3-yloxy)isothiazol-4-yl)picolinamide,N-(5-(azepan-4-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-3-ylmethoxy)isothiazol-4-yl)picolinamide,6-(2,6-difluorophenyl)-5-fluoro-N-(5-(pyrrolidin-3-ylmethoxy)isothiazol-4-yl)picolinamide,N-(5-(azetidin-3-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,N-(5-(((1r,4r)-4-aminocyclohexyl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,N-(5-((3-aminocyclohexyl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,N-(5-(3-aminopropoxyl)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,6-(2,6-difluorophenyl)-5-fluoro-N-(5-(3-(methylamino)propoxy)isothiazol-4-yl)picolinamide,6-(2,6-difluorophenyl)-N-(5-(3-(dimethylamino)propoxy)isothiazol-4-yl)-5-fluoropicolinamide,N-(5-(4-aminobutoxyl)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,6-(2,6-difluorophenyl)-5-fluoro-N-(5-(4-(methylamino)butoxy)isothiazol-4-yl)picolinamide,6-(2,6-difluorophenyl)-5-fluoro-N-(5-(3-hydroxypropoxyl)isothiazol-4-yl)picolinamide,6-(2,6-difluorophenyl)-5-fluoro-N-(5-(3-hydroxybutoxyl)isothiazol-4-yl)picolinamide,6-(2,6-difluorophenyl)-5-fluoro-N-(5-(4-hydroxybutoxyl)isothiazol-4-yl)picolinamide,6-(2,6-difluorophenyl)-5-fluoro-N-(5-((4-hydroxy-4-methylpentyl)oxy)isothiazol-4-yl)picolinamide,6-(2,6-difluorophenyl)-N-(5-(3,4-dihydroxybutoxyl)isothiazol-4-yl)-5-fluoropicolinamide,6-(2,6-difluorophenyl)-5-fluoro-N-(5-((tetrahydro-2H-pyran-4-yl)methoxy)isothiazol-4-yl)picolinamide,3-amino-6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-4-ylmethoxy)isothiazol-4-yl)picolinamide,3-amino-6-(2,6-difluorophenyl)-5-fluoro-N-(5-(pyrrolidin-3-yloxy)isothiazol-4-yl)picolinamide,3-amino-6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-4-yloxy)isothiazol-4-yl)picolinamide,3-amino-N-(5-(azepan-4-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,3-amino-N-(5-(((1r,4r)-4-aminocyclohexyl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,3-amino-6-(2,6-difluorophenyl)-5-fluoro-N-(5-(pyrrolidin-3-ylmethoxy)isothiazol-4-yl)picolinamide,N-(5-((1-amino-3-chloropropan-2-yl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,N-(5-(3-amino-2-(chloromethyl)propoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,3-amino-N-(5-(azetidin-3-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,3-amino-N-(5-(azetidin-3-ylmethoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,3-amino-N-(5-((1-amino-3-chloropropan-2-yl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,3-amino-N-(5-(3-amino-2-(chloromethyl)propoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,3-amino-6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-3-ylmethoxy)isothiazol-4-yl)picolinamide,3-amino-N-(5-(4-aminobutoxyl)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,3-amino-N-(5-((3-aminocyclohexyl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,N-(5-(4-aminobutoxyl)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide,N-(5-(azetidin-3-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide,(S)-6-(2,6-difluorophenyl)-N-(5-(pyrrolidin-3-yloxy)isothiazol-4-yl)picolinamide,6-(2,6-difluorophenyl)-N-(5-(piperidin-4-yloxy)isothiazol-4-yl)picolinamide,N-(5-(azepan-4-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide,N-(5-(azetidin-3-ylmethoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide,6-(2,6-difluorophenyl)-N-(5-(pyrrolidin-3-ylmethoxy)isothiazol-4-yl)picolinamide,6-(2,6-difluorophenyl)-N-(5-(piperidin-4-ylmethoxy)isothiazol-4-yl)picolinamide,N-(5-((1-amino-3-chloropropan-2-yl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide,N-(5-(3-amino-2-(chloromethyl)propoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide,3-amino-N-(5-(4-aminobutoxyl)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide,3-amino-N-(5-(azetidin-3-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide,(S)-3-amino-6-(2,6-difluorophenyl)-N-(5-(pyrrolidin-3-yloxy)isothiazol-4-yl)picolinamide,(R)-3-amino-6-(2,6-difluorophenyl)-N-(5-(pyrrolidin-3-yloxy)isothiazol-4-yl)picolinamide,3-amino-6-(2,6-difluorophenyl)-N-(5-(piperidin-4-yloxy)isothiazol-4-yl)picolinamide,3-amino-N-(5-(azepan-4-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide,3-amino-N-(5-(azetidin-3-ylmethoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide,3-amino-6-(2,6-difluorophenyl)-N-(5-(pyrrolidin-3-ylmethoxy)isothiazol-4-yl)picolinamide,3-amino-6-(2,6-difluorophenyl)-N-(5-(piperidin-4-ylmethoxy)isothiazol-4-yl)picolinamide,3-amino-N-(5-((1-amino-3-chloropropan-2-yl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide,3-amino-N-(5-(3-amino-2-(chloromethyl)propoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide,3-amino-6-(2,6-difluorophenyl)-N-(5-(3-hydroxypropoxyl)isothiazol-4-yl)picolinamide

The present invention also provides the methods of synthesis of theabove PIM kinase inhibitors. The compounds in the present invention aremade from commercially available starting materials and reagents. Thepresent invention is illustrated in the following reaction scheme:

(1) The general procedure for the synthesis of compounds of Formula II

Alcohol B (1 eq.), protected or unprotected, reacts with a base, forexample, NaH (1-3 eq.), in a solvent, for example, THF, at roomtemperature (25° C.) for 1 hour, then reacts with5-bromo-4-nitroisothiazole A (1 eq.) at 25-50° C. for 1-10 hours to formnitroisothiazole ether C. C (1 eq.) is hydrogenated at 1-3 atm ofhydrogen in the presence of 10% Pd/C (0.1-0.5 eq.) in a solvent such as1:1 mixture of methanol and ethylacetate for 4-12 hours to getaminoisothiazole D. Protected or unprotected aromatic carboxylic acid E(1 eq.), in the presence of a coupling reagent, for example, HATU (1-1.5eq.), a base, for example, DIEA (3 eq.), in a solvent, for example DMF,at heated conditions, for example 40° C., reacts with amine D (1 eq.)for 0.5-8 hours to form ether F. If there is no protecting group in E,then E is final ether product of Formula I or II. If F is protected byprotecting group, for example, BOC or trimethylsilyl group, it'sdeprotected by treating with an acid such as trifluoroacetic acid(10-100 eq.) with equal volume of dichloromethane at room temperature(25° C.) for 1-16 hours. The final ether product F of Formula I or II isobtained after removing the solvent in vacuo at room temperature (25°C.).

The present invention also provides the pharmaceutical application ofthe above PIM kinase inhibitors.

The PIM kinase assays show that all compounds in all the examples cansignificantly inhibit the PIM-1, PIM-2 and PIM-3 activity. The IC₅₀ ofthese compounds range from 0.1 nM to 50 nM. Therefore, the PIM kinaseinhibitors in the present invention may be used for pharmaceuticals.

The present invention provides the use of the above PIM kinaseinhibitors as drugs to treat or prevent hematological cancers such ashuman chronic lymphocytic leukemia, Acute Lymphoblastic Leukemia (ALL),Acute Myeloid Leukemia (AML), Chronic myelogenous leukemia (CML),Non-Hodgkin's Lymphoma (NHL) and Multiple Myeloma (MM) and solid tumorssuch as pancreatic cancers, prostate cancers, liver cancers, gastriccancer and bladder cancer, and the PIM kinase inhibitors of the presentinvention further may be used to treat or prevent multi drug resistance,and T cell-mediated diseases such Inflammatory Bowel Disease (IBD). Thepresent invention further provides the use of the PIM kinase inhibitorsof the present invention as drugs to treat or prevent autoimmunediseases.

The drugs in present invention use PIM kinase inhibitors as activeingredients along with pharmaceutical carriers and adjuvants. Thepresent invention provides the new application of PIM kinase inhibitorsand has significant clinical value.

EXAMPLES

The following examples are set forth for illustration only to helpunderstand the invention described herein and not to be construed aslimiting the present invention in any manner.

Example 1 Synthesis of6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-4-ylmethoxy)isothiazol-4-yl)picolinamide(1)

(1) Synthesis of tert-butyl4-(((4-nitroisothiazol-5-yl)oxy)methyl)piperidine-1-carboxylate (C1)

To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate(B1) (250 mg, 1.16 mmol) in THF (5 ml) at room temperature (25° C.) wasadded NaH (33 mg, 1.39 mmol) and stirred at room temperature for 20minutes. 5-bromo-4-nitroisothiazole (A) (242 mg, 1.16 mmol) was added.The reaction mixture was stirred at 50° C. for 5 hours and the solventwas removed in vacuo. The residue was purified with flash chromatographyelueded with 10-30% ethylacetate in petroleum ether to afford a theproduct C1 (247 mg, 0.719 mmol)

(2) tert-butyl4-(((4-aminoisothiazol-5-yl)oxy)methyl)piperidine-1-carboxylate (D1)

To a solution of C1 (200 mg, 0.582 mmol) in a mixed solvent of methanol(2 ml) and ethylacetate (2 ml) at room temperature (25° C.) was added10% Pd/C. The mixture was stirred under hydrogen (1 atm) for 10 hours.The mixture was then filtered and the filtrate was concentrated to yieldthe product D1 (167 mg, 0.534 mmol)

(3) Synthesis of tert-butyl4-(((4-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)isothiazol-5-yl)oxy)methyl)piperidine-1-carboxylate(Boc-F1)

Compound (D1) (50 mg, 0.16 mmol),6-(2,6-difluorophenyl)-5-fluoropicolinic acid (E1) (40 mg, 0.16 mmol,HATU (72 mg, 0.19 mmol) and DIEA (88 μL, 0.507 mmol) are mixed in DMF (5mL) and stirred at 50° C. for 1 hour. The reaction mixture was cooled toroom temperature and diluted with ethyl acetate (50 mL), washed withbrine, dried over Na₂SO₄, and concentrated in vacuo. The residue waspurified with flash column (eluent: 10-30% ethyl acetate/petroleumether) to obtain the product Boc-F1 (31 mg, 0.056 mmol).

(4) Synthesis of6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-4-ylmethoxy)isothiazol-4-yl)picolinamide(1)

At room temperature, TFA (trifluoroacetic acid) (0.5 mL) was added to asolution of Compound Boc-F1 (20 mg, 0.036 mmol) in CH₂Cl₂ (1 mL) andstirred for 10 min. The mixture was the concentrated in vacuo. Theresidue was dissolved in CH₂Cl₂ (10 mL) and washed with NaOH (5 mL) andbrine (5 mL), dried over Na₂SO₄, and concentrated in vacuo to obtain thetitle compound 1 (10 mg, 0.022 mmol).

Example 2 Synthesis ofN-(5-(azetidin-3-ylmethoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide(2)

Following the procedure described in Example 1, and substitutingcompound B1 in Step (1) with tert-butyl3-(hydroxymethyl)azetidine-1-carboxylate (B2), the title compound 2 wasobtained.

Example 3 Synthesis of6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-4-yloxy)isothiazol-4-yl)picolinamide(3)

Following the procedure described in Example 1, and substitutingcompound B1 in Step (1) with tert-butyl4-hydroxypiperidine-1-carboxylate (B3), the title compound 3 wasobtained.

Example 4 Synthesis of6-(2,6-difluorophenyl)-5-fluoro-N-(5-(pyrrolidin-3-yloxy)isothiazol-4-yl)picolinamide(4)

Following the procedure described in Example 1, and substitutingCompound B1 in Step (1) with tert-butyl3-hydroxypyrrolidine-1-carboxylate (B4), the title compound 4 wasobtained.

Example 5 Synthesis of6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-3-yloxy)isothiazol-4-yl)picolinamide(5)

Following the procedure described in Example 1, and substitutingCompound B1 in Step (1) with tert-butyl3-hydroxypiperidine-1-carboxylate (B5), the title compound 5 wasobtained.

Example 6 Synthesis ofN-(5-(azepan-4-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide(6)

Following the procedure described in Example 1, and substitutingCompound B1 in Step (1) with tert-butyl 4-hydroxyazepane-1-carboxylate(B6), the title compound 6 was obtained.

Example 7 Synthesis of6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-3-ylmethoxy)isothiazol-4-yl)picolinamide(7)

Following the procedure described in Example 1, and substitutingCompound B1 in Step (1) with tert-butyl3-(hydroxymethyl)piperidine-1-carboxylate (B7), the title compound 7 wasobtained.

Example 8 Synthesis of6-(2,6-difluorophenyl)-5-fluoro-N-(5-(pyrrolidin-3-ylmethoxy)isothiazol-4-yl)picolinamide(8)

Following the procedure described in Example 1, and substitutingCompound B1 in Step (1) with tert-butyl3-(hydroxymethyl)pyrrolidine-1-carboxylate (B8), the title compound 8was obtained.

Example 9 Synthesis ofN-(5-(azetidin-3-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide(9)

Following the procedure described in Example 1, and substitutingCompound B1 in Step (1) with tert-butyl3-(hydroxymethyl)azetidine-1-carboxylate (B9), the title compound 9 wasobtained.

Example 10 Synthesis ofN-(5-(((1r,4r)-4-aminocyclohexyl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide(10)

Following the procedure described in Example 1, and substitutingCompound B1 in Step (1) with tert-butyl((1r,4r)-4-hydroxycyclohexyl)carbamate (B10), the title compound 10 wasobtained.

Example 11 Synthesis ofN-(5-((3-aminocyclohexyl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide(11)

Following the procedure described in Example 1, and substitutingCompound 1E in Step (1) with tert-butyl(3-hydroxycyclohexyl)carbamate(B11), the title compound 11 was obtained.

Example 12 Synthesis ofN-(5-(3-aminopropoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide(12)

Following the procedure described in Example 1, and substitutingCompound B1 in Step (1) with tert-butyl(3-hydroxypropyl)carbamate (B12),the title compound 12 was obtained.

Example 13 Synthesis of6-(2,6-difluorophenyl)-5-fluoro-N-(5-(3-(methylamino)propoxy)isothiazol-4-yl)picolinamide(13)

Following the procedure described in Example 1, and substitutingCompound B1 in Step (1) with 3-(methylamino)propan-1-ol (B13), the titlecompound 13 was obtained.

Example 14 Synthesis of6-(2,6-difluorophenyl)-N-(5-(3-(dimethylamino)propoxy)isothiazol-4-yl)-5-fluoropicolinamide(14)

Following the procedure described in Example 1, and substitutingCompound B1 in Step (1) with 3-(dimethylamino)propan-1-ol (B14), thetitle compound 14 was obtained.

Example 15

Synthesis ofN-(5-(4-aminobutoxyl)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide(15)

Following the procedure described in Example 1, and substitutingCompound B1 in Step (1) with tert-butyl(4-hydroxybutyl)carbamate (B15),the title compound 15 was obtained.

Example 16 Synthesis of6-(2,6-difluorophenyl)-5-fluoro-N-(5-(4-(methylamino)butoxy)isothiazol-4-yl)picolinamide(16)

Following the procedure described in Example 1, and substitutingCompound B1 in Step (1) with tert-butyl(4-hydroxybutyl)(methyl)carbamate(B16), the title compound 16 was obtained.

Example 17 Synthesis of6-(2,6-difluorophenyl)-5-fluoro-N-(5-(3-hydroxypropoxyl)isothiazol-4-yl)picolinamide(17)

Following the procedure described in Example 1, and substitutingCompound B1 in Step (1) with propane-1,3-diol (B17), the title compound17 was obtained.

Example 18 Synthesis of6-(2,6-difluorophenyl)-5-fluoro-N-(5-(3-hydroxybutoxyl)isothiazol-4-yl)picolinamide(18)

Following the procedure described in Example 1, and substitutingCompound B1 in Step (1) with butane-1,3-diol (B18), the title compound18 was obtained.

Example 19 Synthesis of6-(2,6-difluorophenyl)-5-fluoro-N-(5-(4-hydroxybutoxyl)isothiazol-4-yl)picolinamide(19)

Following the procedure described in Example 1, and substitutingCompound B1 in Step (1) with butane-1,4-diol (B4), the title compound 19was obtained.

Example 20 Synthesis of6-(2,6-difluorophenyl)-5-fluoro-N-(5-((4-hydroxy-4-methylpentyl)oxy)isothiazol-4-yl)picolinamide(20)

Following the procedure described in Example 1, and substitutingCompound B1 in Step (1) with 4-methylpentane-1,4-diol (20), the titlecompound 20 was obtained.

Example 21 Synthesis of6-(2,6-difluorophenyl)-N-(5-(3,4-dihydroxybutoxyl)isothiazol-4-yl)-5-fluoropicolinamide(21)

(1) Synthesis of6-(2,6-difluorophenyl)-N-(5-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)isothiazol-4-yl)-5-fluoropicolinamide(Protect F21)

Following the procedure described in Example 1, Step (1) and (2), andsubstituting Compound B1 in Step (1) with2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol (B21), compound Protectd F21was obtained.

(2) Synthesis of6-(2,6-difluorophenyl)-N-(5-(3,4-dihydroxybutoxyl)isothiazol-4-yl)-5-fluoropicolinamide(21)

At room temperature (25° C.), Procted E21 (20 mg, 0.042 mmol) inmethanol (2 mL) was added concentrated HCl (0.5 mL) and the solution wasstirred for 4 hours. 10% Na₂CO₃ solution was added to neutralize thesolution to pH=7, the water (20 mL) was added and a precipitate wasformed. An off white solid product title compound 21 (14 mg, 0.032 mmol)was obtained after filtration and air drying at 25° C.

Example 22 Synthesis of6-(2,6-difluorophenyl)-5-fluoro-N-(5-((tetrahydro-2H-pyran-4-yl)methoxy)isothiazol-4-yl)picolinamide(22)

Following the procedure described in Example 1, and substitutingCompound B1 in Step (1) with (tetrahydro-2H-pyran-4-yl)methanol (B22),the title compound 22 was obtained.

Example 23 Synthesis of3-amino-6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-4-ylmethoxy)isothiazol-4-yl)picolinamide(23)

Following the procedure described in Example 1, and substitutingCompound E1 in Step (3) with3-amino-6-(2,6-difluorophenyl)-5-fluoropicolinic acid (E2), the titlecompound 23 was obtained.

Example 24 Synthesis of3-amino-6-(2,6-difluorophenyl)-5-fluoro-N-(5-(pyrrolidin-3-yloxy)isothiazol-4-yl)picolinamide(24)

Following the procedure described in Example 23, and substitutingCompound B1 in Step (1) with B4, the title compound 24 was obtained.

Example 25 Synthesis of3-amino-6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-4-yloxy)isothiazol-4-yl)picolinamide(25)

Following the procedure described in Example 23, and substitutingCompound B1 in Step (1) with B3, the title compound 25 was obtained.

Example 26 Synthesis of3-amino-N-(5-(azepan-4-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide(26)

Following the procedure described in Example 23, and substitutingCompound B1 in Step (1) with B6, the title compound 26 was obtained.

Example 27 Synthesis of3-amino-N-(5-(((1r,4r)-4-aminocyclohexyl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide(27)

Following the procedure described in Example 23, and substitutingCompound B1 in Step (1) with B10, the title compound 27 was obtained.

Example 28 Synthesis of3-amino-6-(2,6-difluorophenyl)-5-fluoro-N-(5-(pyrrolidin-3-ylmethoxy)isothiazol-4-yl)picolinamide(28)

Following the procedure described in Example 23, and substitutingCompound B1 in Step (1) with B8, the title compound 28 was obtained.

Example 29 Synthesis ofN-(5-((1-amino-3-chloropropan-2-yl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide(29)

To a solution of 4M HCl in methanol (1 mL) at room temperature was addedcompound 9 (20 mg, 0.049 mmol). The solution was stirred for 4 hours.The solvent was then removed and the residue was washed with ether andthen dried under vacuo to get an off white solid product 29 (20 mg,0.045 mmol)

Example 30 Synthesis ofN-(5-(3-amino-2-(chloromethyl)propoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide(30)

Following the procedure described in Example 29, and substitutingCompound 9 with 2, the title compound 30 was obtained.

Example 31 Synthesis of3-amino-N-(5-(azetidin-3-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide(31)

Following the procedure described in Example 23, and substitutingCompound B1 in Step (1) with B9, the title compound 31 was obtained.

Example 32 Synthesis of3-amino-N-(5-(azetidin-3-ylmethoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide(32)

Following the procedure described in Example 23, and substitutingCompound B1 in Step (1) with B2, the title compound 32 was obtained.

Example 33 Synthesis of3-amino-N-(5-((1-amino-3-chloropropan-2-yl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide(33)

Following the procedure described in Example 29, and substitutingCompound 9 with 31, the title compound 33 was obtained.

Example 34 Synthesis of3-amino-N-(5-(3-amino-2-(chloromethyl)propoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide(34)

Following the procedure described in Example 29, and substitutingCompound 9 with 32, the title compound 34 was obtained.

Example 35 Synthesis of3-amino-6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-3-ylmethoxy)isothiazol-4-yl)picolinamide(35)

Following the procedure described in Example 23, and substitutingCompound B1 in Step (1) with B7, the title compound 35 was obtained.

Example 36 Synthesis of3-amino-N-(5-(4-aminobutoxyl)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide(36)

Following the procedure described in Example 23, and substitutingCompound B1 in Step (1) with B15, the title compound 36 was obtained.

Example 37 Synthesis of3-amino-N-(5-((3-aminocyclohexyl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide(37)

Following the procedure described in Example 23, and substitutingCompound B1 in Step (1) with B11, the title compound 37 was obtained.

Example 38 Synthesis ofN-(5-(4-aminobutoxyl)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide(38)

Following the procedure described in Example 1, and substitutingCompound B1 in Step (1) with B15 and Compound E1 in Step (3) with6-(2,6-difluorophenyl)picolinic acid (E3), the title compound 38 wasobtained.

Example 39 Synthesis ofN-(5-(azetidin-3-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide(39)

Following the procedure described in Example 38, and substitutingCompound B15 in Step (1) with B9, the title compound 39 was obtained.

Example 40 Synthesis of(S)-6-(2,6-difluorophenyl)-N-(5-(pyrrolidin-3-yloxy)isothiazol-4-yl)picolinamide(40)

Following the procedure described in Example 38, and substitutingCompound B15 in Step (1) with (5)-tert-butyl3-hydroxypyrrolidine-1-carboxylate (B40), the title compound 40 wasobtained.

Example 41 Synthesis of6-(2,6-difluorophenyl)-N-(5-(piperidin-4-yloxy)isothiazol-4-yl)picolinamide(41)

Following the procedure described in Example 38, and substitutingCompound B15 in Step (1) with B3, the title compound 41 was obtained.

Example 42 Synthesis ofN-(5-(azepan-4-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide(42)

Following the procedure described in Example 38, and substitutingCompound B15 in Step (1) with B6, the title compound 41 was obtained.

Example 43 Synthesis ofN-(5-(azetidin-3-ylmethoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide(43)

Following the procedure described in Example 38, and substitutingCompound B15 in Step (1) with B2, the title compound 43 was obtained.

Example 44 Synthesis of6-(2,6-difluorophenyl)-N-(5-(pyrrolidin-3-ylmethoxy)isothiazol-4-yl)picolinamide(44)

Following the procedure described in Example 38, and substitutingCompound B15 in Step (1) with B8, the title compound 44 was obtained.

Example 45 Synthesis of6-(2,6-difluorophenyl)-N-(5-(piperidin-4-ylmethoxy)isothiazol-4-yl)picolinamide(45)

Following the procedure described in Example 38, and substitutingCompound B15 in Step (1) with B1, the title compound 45 was obtained.

Example 46 Synthesis ofN-(5-((1-amino-3-chloropropan-2-yl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide(46)

Following the procedure described in Example 29, and substitutingCompound 9 with 39, the title compound 46 was obtained.

Example 47 Synthesis ofN-(5-(3-amino-2-(chloromethyl)propoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide(47)

Following the procedure described in Example 29, and substitutingCompound 9 with 43, the title compound 47 was obtained.

Example 48 Synthesis of3-amino-N-(5-(4-aminobutoxyl)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide(48)

Following the procedure described in Example 1, and substitutingCompound B1 in Step (1) with B15 and Compound E1 in Step (3) with3-amino-6-(2,6-difluorophenyl)picolinic acid (E4), the title compound 48was obtained.

Example 49 Synthesis of3-amino-N-(5-(azetidin-3-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide(49)

Following the procedure described in Example 48, and substitutingCompound B15 in Step (1) with B9, the title compound 49 was obtained.

Example 50 Synthesis of(S)-3-amino-6-(2,6-difluorophenyl)-N-(5-(pyrrolidin-3-yloxy)isothiazol-4-yl)picolinamide(50)

Following the procedure described in Example 48, and substitutingCompound B15 in Step (1) with B40, the title compound 49 was obtained.

Example 51 Synthesis of(R)-3-amino-6-(2,6-difluorophenyl)-N-(5-(pyrrolidin-3-yloxy)isothiazol-4-yl)picolinamide(51)

Following the procedure described in Example 48, and substitutingCompound B15 in Step (1) with (R)-tert-butyl3-hydroxypyrrolidine-1-carboxylate (B51), the title compound 51 wasobtained.

Example 52 Synthesis of3-amino-6-(2,6-difluorophenyl)-N-(5-(piperidin-4-yloxy)isothiazol-4-yl)picolinamide(52)

Following the procedure described in Example 48, and substitutingCompound B15 in Step (1) with B3, the title compound 52 was obtained.

Example 53 Synthesis of3-amino-N-(5-(azepan-4-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide(53)

Following the procedure described in Example 48, and substitutingCompound B15 in Step (1) with B6, the title compound 53 was obtained.

Example 54 Synthesis of3-amino-N-(5-(azetidin-3-ylmethoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide(54)

Following the procedure described in Example 48, and substitutingCompound B15 in Step (1) with B2, the title compound 54 was obtained.

Example 55 Synthesis of3-amino-6-(2,6-difluorophenyl)-N-(5-(pyrrolidin-3-ylmethoxy)isothiazol-4-yl)picolinamide(55)

Following the procedure described in Example 48, and substitutingCompound B15 in Step (1) with B8, the title compound 55 was obtained.

Example 56 Synthesis of3-amino-6-(2,6-difluorophenyl)-N-(5-(piperidin-4-ylmethoxy)isothiazol-4-yl)picolinamide(56)

Following the procedure described in Example 48, and substitutingCompound B15 in Step (1) with B1, the title compound 56 was obtained.

Example 57 Synthesis of3-amino-N-(5-((1-amino-3-chloropropan-2-yl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide(57)

Following the procedure described in Example 29, and substitutingCompound 9 with 49, the title compound 57 was obtained.

Example 58 Synthesis of3-amino-N-(5-(3-amino-2-(chloromethyl)propoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide(58)

Following the procedure described in Example 29, and substitutingCompound 9 with 54, the title compound 58 was obtained.

Example 59 Synthesis of3-amino-6-(2,6-difluorophenyl)-N-(5-(3-hydroxypropoxy)isothiazol-4-yl)picolinamide(59)

Following the procedure described in Example 48, and substitutingCompound B17 in Step (1) with B8, the title compound 59 was obtained.

TABLE I Analytical data of the compounds described in the examples ofthe present invention Name NMR MS 6-(2,6-difluorophenyl)-5-fluoro-N- 1HNMR (400 MHz, DMSO-d6) δ: 1.34 (bs, 2H), 1.78 (bs, 2H), 449(M + 1)(5-(piperidin-4- 2.69 (bs, 3H), 3.12 (bs, 2H), 4.11 (bs, 2H), 7.37 (t, J= 8, 2H), ylmethoxy)isothiazol-4- 7.67-7.75 (m, 1H), 8.21 (t, J = 10,1H), 8.35 (dd, J = 8, 4, 1H), 8.54 yl)picolinamide (s, 1H), 8.60 (bs,1H), 8.75 (bs, 1H), 10.10 (s, 1H) N-(5-(azetidin-3- 1H NMR (400 MHz,CDCl3) δ: 1.99 (bs, 1H), 3.60-4.40 (m, 4H), 421(M + 1)ylmethoxy)isothiazol-4-yl)-6-(2,6- 4.45 (bs, 2H), 7.11 (t, J = 8, 2H),7.45-7.65 (m, 1H), 7.69 (t, J = 8, difluorophenyl)-5- 1H), 8.29 (dd, J =8, 4, 1H), 8.86 (bs, 1H), 9.49 (bs, 1H) fluoropicolinamide6-(2,6-difluorophenyl)-5-fluoro-N- 1H NMR (400 MHz, DMSO-d6) δ:1.95-2.05 (m, 2H). 2.10-2.20 435(M + 1)(5-(piperidin-4-yloxy)isothiazol-4- (m, 2H), 3.11-3.13- (m, 2H),3.23-3.25 (m, 2H), 4.58-4.60 (m, yl)picolinamide 1H), 7.38 (t, J = 8,2H), 7.68-7.74 (m, 1H), 8.21 (t, J = 10, 1H), 8.33 (dd, J = 8, 4, 1H),8.53 (s, 1H), 8.65 (bs, 2H), 10.11 (s, 1H),6-(2,6-difluorophenyl)-5-fluoro-N- 1H NMR (400 MHz, DMSO-d6) δ:2.05-2.35 (m, 4H), 5.12 (bs, 421(M + 1)(5-(pyrrolidin-3-yloxy)isothiazol-4- 1H), 5.26 (s, 1H), 7.37 (t, J = 8,2H), 7.67-7.75 (m, 1H), 8.21 (t, yl)picolinamide J = 10, 1H), 8.35 (dd,J = 8, 4, 1H), 9.39 (bs, 1H), 9.86 (bs, 1H), 10.11 (s, 1H)6-(2,6-difluorophenyl)-5-fluoro-N- 1H NMR (400 MHz, DMSO-d6) δ:1.60-1.80 (m, 1H), 1.80-2.01 435(M + 1)(5-(piperidin-3-yloxy)isothiazol-4- (m, 3H), 3.05 (bs, 2H), 3.57 (s,2H), 4.67 (bs, 1H), 7.37 (t, J = 8, yl)picolinamide 2H), 7.67-7.75 (m,1H), 8.21 (t, J = 10, 1H), 8.35 (dd, J = 8, 4, 1H), 8.67 (s, 1H), 8.80(bs, 1H), 9.34 (bs, 1H), 10.18 (s, 1H)N-(5-(azepan-4-yloxy)isothiazol-4- 1H NMR (400 MHz, DMSO-d6) δ:1.70-2.40 (m, 6H), 3.00-3.30 449(M + 1) yl)-6-(2,6-difluorophenyl)-5-(m, 4H), 4.59 (bs, 1H), 7.39 (t, J = 8, 2H), 7.67-7.75 (m, 1H), 8.21fluoropicolinamide (t, J = 10, 1H), 8.33 (dd, J = 8, 4, 1H), 8.57 (s,1H), 9.09 (bs, 1H), 9.18 (bs, 1H), 10.02 (s, 1H)6-(2,6-difluorophenyl)-5-fluoro-N- 1H NMR (400 MHz, DMSO-d6) δ:1.30-1.40 (m, 1H), 1.55-1.75 449(M + 1) (5-(piperidin-3- (m, 1H),1.75-1.85 (m, 2H), 2.70-2.90 (m, 1H), 3.25 (d, j = 8, 2H),ylmethoxy)isothiazol-4- 4.18 (bs, 2H), 7.38 (t, J = 8, 2H), 7.67-7.75(m, 1H), 8.20 (t, J = 10, yl)picolinamide 1H), 8.33 (dd, J = 8, 4, 1H),8.54 (bs, 2H), 8.75 (bs, 1H), 10.05 (s, 1H)6-(2,6-difluorophenyl)-5-fluoro-N- 1H NMR (400 MHz, CDCl3) δ: 2.00 (bs,1H), 2.31 (bs, 12H), 435(M + 1) (5-(pyrrolidin-3- 2.99 (bs, 1H),3.20-3.60 (m, 4H), 4.26 (bs, 2H), 7.17 (t, J = 8, 2H),ylmethoxy)isothiazol-4- 7.45-7.60 (m, 1H), 7.77 (t, J = 8, 1H), 8.40(bs, 1H), 8.91 (s, 1H), yl)picolinamide 9.56 (s, 1H)N-(5-(azetidin-3-yloxy)isothiazol-4- 1H NMR (400 MHz, CDCl3) δ:3.10-3.60 (m, 3H), 3.95-4.40 (m, 407(M + 1)yl)-6-(2,6-difluorophenyl)-5- 1H), 4.80-5.20 (m, 1H), 7.11 (t, J = 8,2H), 7.45-7.65 (m, 1H), 7.76 fluoropicolinamide (t, J = 8, 1H), 8.40(dd, J = 8, 4, 1H), 9.03 (s, 0.7H), 9.08 (s, 0.3H), 9.53 (bs, 1H)N-(5-(((1r,4r)-4- 1H NMR (400 MHz, DMSO) δ: 1.10-1.51 (m, 2H), 1.64-1.69(m, 449(M + 1) aminocyclohexyl)oxy)isothiazol-4- 2H), 1.98-2.02 (m, 2H),2.20-2.23 (m, 2H), 2.84-2.90 (m, 1H), yl)-6-(2,6-difluorophenyl)-5-4.35-4.41 (m, 1H), 7.38 (t, J = 8, 2H), 7.67-7.75 (m, 1H), 8.20 (t,fluoropicolinamide J = 10, 1H), 8.33 (dd, J = 8, 4, 1H), 8.55 (s, 1H),8.95 (bs, 1H), 9.10 (bs, 1H), 10.13 (s, 1H) N-(5-((3- 1H NMR (400 MHz,CDCl3) δ: 1.05-2.00 (m, 5H), 2.60-2.80 (m, 449(M + 1)aminocyclohexyl)oxy)isothiazol-4- 3H), 3.05-3.50 (m, 1H), 3.95-4.05 (m,0.7H), 4.48 (bs, 0.3H), yl)-6-(2,6-difluorophenyl)-5- 7.01 (t, J = 8,2H), 7.60-7.70 (m, 1H), 8.29 (dd, J = 8, 4, 1H), 8.97 fluoropicolinamide(s, 0.7H), 9.03 (s, 0.3H), 9.52 (bs, 1H)N-(5-(3-aminopropoxy)isothiazol-4- 1H NMR (400 MHz, CD3OD) δ: 1.86 (bs,2H), 2.81 (bs, 2H), 409(M + 1) yl)-6-(2,6-difluorophenyl)-5- 4.21 (bs,2H), 7.30 (t, J = 8, 2H), 7.57-7.77 (m, 1H), 8.05 (t, J = 8,fluoropicolinamide 1H), 8.40 (dd, J = 8, 4, 1H), 9.10 (s, 1H)6-(2,6-difluorophenyl)-5-fluoro-N- 1H NMR (400 MHz, CD3OD) δ: 1.91 (bs,2H), 2.81 (bs, 2H), 423(M + 1) (5-(3- 2.85 (s, 3H), 4.22 (bs, 2H), 7.29(t, J = 8, 2H), 7.56-7.75 (m, 1H), (methylamino)propoxy)isothiazol-4-8.15 (t, J = 8, 1H), 8.41 (dd, J = 8, 4, 1H), 9.08 (s, 1H)yl)picolinamide 6-(2,6-difluorophenyl)-N-(5-(3- 1H NMR (400 MHz, CD3OD)δ: 1.90 (bs, 2H), 2.80 (bs, 2H), 437(M + 1)(dimethylamino)propoxy)isothiazol- 2.90 (s, 6H), 4.20 (bs, 2H), 7.31 (t,J = 8, 2H), 7.55-7.75 (m, 1H), 4-yl)-5-fluoropicolinamide 8.21 (t, J =8, 1H), 8.40 (dd, J = 8, 4, 1H), 9.11 (s, 1H)N-(5-(4-aminobutoxy)isothiazol-4- 1H NMR (400 MHz, CD3OD) δ: 1.51-1.60(m, 2H), 1.75-1.79 443(M + 1) yl)-6-(2,6-difluorophenyl)-5- (m, 2H),2.81-2.83 (m, 2H), 4.21 (t, J = 8 Hz, 2H), 7.32 (t, J = 8,fluoropicolinamide 2H), 7.55-7.75 (m, 1H), 8.20 (t, J = 8, 1H), 8.39(dd, J = 8, 4, 1H), 9.12 (s, 1H) 6-(2,6-difluorophenyl)-5-fluoro-N- 1HNMR (400 MHz, CD3OD) δ: 1.50-1.61 (m, 2H), 1.75-1.80 437(M + 1) (5-(4-(m, 2H), 2.81-2.83 (m, 2H), 2.92 (s, 3H), 4.21 (t, J = 8 Hz, 2H),(methylamino)butoxy)isothiazol-4- 7.30 (t, J = 8, 2H), 7.55-7.75 (m,1H), 8.21 (t, J = 8, 1H), 8.40 (dd, yl)picolinamide J = 8, 4, 1H), 9.09(s, 1H) 6-(2,6-difluorophenyl)-5-fluoro-N- 1H NMR (400 MHz, DMSO-d6) δ:1.90 (bs, 2H), 3.66 (bs, 2H), 410(M + 1)(5-(3-hydroxypropoxy)isothiazol-4- 4.27 (bs, 2H), 4.63 (s, 1H), 7.38 (t,J = 8, 2H), 7.65-7.75 (m, 1H), yl)picolinamide 8.20 (t, J = 8, 1H), 8.32(dd, J = 8, 4, 1H), 8.56 (s, H), 10.10 (s, 1H)6-(2,6-difluorophenyl)-5-fluoro-N- 1H NMR (400 MHz, CD3OD) δ: 1.02 (s,3H), 1.60-1.78 (m, 2H), 424(M + 1) (5-(3-hydroxybutoxy)isothiazol-4-3.40-3.55 (m, 1H), 4.10-4.25 (m, 2H), 7.30 (t, J = 8, 2H), 7.55-7.75yl)picolinamide (m, 1H), 8.21 (t, J = 8, 1H), 8.39 (dd, J = 8, 4, 1H),9.10 (s, 1H) 6-(2,6-difluorophenyl)-5-fluoro-N- 1H NMR (400 MHz, CD3OD)δ: 1.45-1.52 (m, 2H), 1.74-1.78 424(M + 1)(5-(4-hydroxybutoxy)isothiazol-4- (m, 2H), 3.36-3.45 (m, 2H), 4.21 (t, J= 8, 2H), 7.30 (t, J = 8, 2H), yl)picolinamide 7.55-7.75 (m, 1H), 8.21(t, J = 8, 1H), 8.40 (dd, J = 8, 4, 1H), 9.09 (s, 1H)6-(2,6-difluorophenyl)-5-fluoro-N- 1H NMR (400 MHz, CD3OD) δ: 1.00 (s,6H), 1.45-1.52 (t, J = 8, 452(M + 1) (5-((4-hydroxy-4- 2H), 1.75-1.78(m, 2H), 4.21 (t, J = 8, 2H), 7.30 (t, J = 8, 2H), 7.55-methylpentyl)oxy)isothiazol-4- 7.75 (m, 1H), 8.20 (t, J = 8, 1H), 8.41(dd, J = 8, 4, 1H), 9.10 (s, 1H) yl)picolinamide6-(2,6-difluorophenyl)-N-(5-(3,4- 1H NMR (400 MHz, CD3OD) δ: 1.88-2.05(m, 2H), 3.28 (bs, 440(M + 1) dihydroxybutoxy)isothiazol-4-yl)-5- 2H),3.70 (bs, 1H), 4.15-4.35 (m, 2H), 7.31 (t, J = 8, 2H), 7.56-fluoropicolinamide 7.75 (m, 1H), 8.20 (t, J = 8, 1H), 8.39 (dd, J = 8,4, 1H), 9.11 (s, 1H) 6-(2,6-difluorophenyl)-5-fluoro-N- 1H NMR (400 MHz,DMSO-d6) δ: 1.68-1.85 (m, 1H), 2.23-2.38 450(M + 1)(5-((tetrahydro-2H-pyran-4- (m, 2H), 2.60-2.70 (m, 2H), 3.75-3.85 (m,2H), 3.97-4.05 (m, yl)methoxy)isothiazol-4- 4H), 7.38 (t, J = 8, 2H),7.67-7.75 (m, 1H), 8.20 (t, J = 10, 1H), 8.32 yl)picolinamide (dd, J =8, 4, 1H), 8.56 (s, 1H), 10.10 (s, 1H) 3-amino-6-(2,6-difluorophenyl)-5-1H NMR (400 MHz, DMSO-d6) δ: 1.34 (bs, 2H), 1.78 (bs, 2H), 464(M + 1)fluoro-N-(5-(piperidin-4- 2.69 (bs, 3H), 3.12 (bs, 2H), 4.11 (bs, 2H),7.22 (bs, 2H), 7.37 (t, ylmethoxy)isothiazol-4- J = 8, 2H), 7.52-7.62(m, 1H), 8.40 (d, J = 10, 1H), 8.80 (s, 1H), yl)picolinamide 9.36 (bs,1H), 9.66 (bs, 1H), 10.12 (s, 1H) 3-amino-6-(2,6-difluorophenyl)-5- 1HNMR (400 MHz, DMSO-d6) δ: 2.05-2.35 (m, 4H), 5.12 (bs, 436(M + 1)fluoro-N-(5-(pyrrolidin-3- 1H), 5.26 (s, 1H), 7.23 (bs, 2H), 7.36 (t, J= 8, 2H), 7.50-7.60 (m, yloxy)isothiazol-4-yl)picolinamide 1H), 8.41 (d,J = 10, 1H), 8.80 (s, 1H), 9.06 (bs, 1H), 9.32 (bs, 1H), 10.11 (s, 1H)3-amino-6-(2,6-difluorophenyl)-5- 1H NMR (400 MHz, DMSO-d6) δ: 1.95-2.05(m, 2H). 2.10-2.20 450(M + 1) fluoro-N-(5-(piperidin-4- (m, 2H),3.11-3.13- (m, 2H), 3.23-3.25 (m, 2H), 4.58-4.60 (m,yloxy)isothiazol-4-yl)picolinamide 1H), 7.20 (bs, 2H), 7.36 (t, J = 8,2H), 7.51-7.62 (m, 1H), 8.41 (d, J = 10, 1H), 8.81 (s, 1H), 9.16 (bs,1H), 9.30 (bs, 1H), 10.10 (s, 1H) 3-amino-N-(5-(azepan-4- 1H NMR (400MHz, DMSO-d6) δ: 1.70-2.40 (m, 6H), 3.00-3.30 464(M + 1)yloxy)isothiazol-4-yl)-6-(2,6- (m, 4H), 4.59 (bs, 1H), 7.22 (bs, 2H),7.36 (t, J = 8, 2H), 7.55-7.65 difluorophenyl)-5- (m, 1H), 8.41 (d, J =10, 1H), 8.80 (s, 1H), 9.18 (bs, 1H), 9.30 (bs, fluoropicolinamide 1H),10.10 (s, 1H) 3-amino-N-(5-(((1r,4r)-4- 1H NMR (400 MHz, DMSO) δ:1.10-1.51 (m, 2H), 1.64-1.69 (m, 464(M + 1)aminocyclohexyl)oxy)isothiazol-4- 2H), 1.98-2.02 (m, 2H), 2.20-2.23 (m,2H), 2.84-2.90 (m, 1H), yl)-6-(2,6-difluorophenyl)-5- 4.35-4.41 (m, 1H),7.22 (bs, 2H), 7.36 (t, J = 8, 2H), 7.54-7.65 (m, fluoropicolinamide1H), 8.05 (bs, 3H), 8.41 (d, J = 10, 1H), 8.81 (s, 1H), 10.09 (s, 1H)3-amino-6-(2,6-difluorophenyl)-5- 1H NMR (400 MHz, DMSO-d6) δ: 1.65-1.74(m, 1H), 2.10-2.17 450(M + 1) fluoro-N-(5-(pyrrolidin-3- (m, 1H),2.70-2.78 (m, 1H), 2.83-2.97 (m, 2H), 3.02-3.08 (m,ylmethoxy)isothiazol-4- 1H), 3.16-3.21 (m, 1H), 4.43-4.45 (m, 2H),7.20-7.31 (m, 3H), yl)picolinamide 7.35 (d, 1H), 7.36 (bs, 2H),7.50-7.62 (m, 1H), 8.43 (dd, J = 8, 4, 1H), 8.81 (s, 1H), 9.04 (bs, 2H),10.18 (s, 1H) N-(5-((1-amino-3-chloropropan-2- 1H NMR (400 MHz, CDCl3)δ: 2.23 (bs, 3H), 3.14 (dd, J = 12, 8, 443(M + 1)yl)oxy)isothiazol-4-yl)-6-(2,6- 1H), 3.23 (dd, J = 10, 4, 1H), 3.51 (s,1H), 3.78 (d, J = 8, 2H), 4.15- difluorophenyl)-5- 4.31 (m, 1H), 7.10(t, J = 8, 2H), 7.46-7.53 (m, 1H), 7.74 (t, J = 10, fluoropicolinamide1H), 8.40 (dd, J = 8, 4, 1H), 9.08 (s, 1H), 10.05 (bs, 1H)N-(5-(3-amino-2- 1H NMR (400 MHz, CDCl3) δ: 2.30-2.70 (m, 4H), 2.90-3.05(m, 457(M + 1) (chloromethyl)propoxy)isothiazol-4- 1H), 3.65 (s, 1H),3.79 (d, J = 8, 2H), 4.20-4.40 (m, 2H), 7.12 (t,yl)-6-(2,6-difluorophenyl)-5- J = 8, 2H), 7.46-7.53 (m, 1H), 7.74 (t, J= 10, 1H), 8.39 (dd, J = 8, 4, fluoropicolinamide 1H), 9.65 (bs, 1H)3-amino-N-(5-(azetidin-3- 1H NMR (400 MHz, DMSO-d6) δ: 3.97-4.00 (m,2H), 4.49-4.52 421(M + 1) yloxy)isothiazol-4-yl)-6-(2,6- (m, 2H),5.40-5.41 (m, 1H), 7.20-7.30 (m, 2H), 7.30 (d, 1H), 7.36difluorophenyl)-5- (bs, 2H), 7.50-7.60 (m, 1H), 8.40 (dd, J = 8, 4, 1H),8.75 (s, 1H), fluoropicolinamide 9.45 (bs, 2H), 10.45 (s, 1H)3-amino-N-(5-(azetidin-3- 1H NMR (400 MHz, DMSO-d6) δ: 2.00-2.01 (m,1H), 3.65-4.35 436(M + 1) ylmethoxy)isothiazol-4-yl)-6-(2,6- (m, 4H),4.63 (d, J = 6, 2H), 7.20-7.30 (m, 2H), 7.34-7.36 (m,,difluorophenyl)-5- 2H), 7.52-7.62 (m, 1H), 8.39 (dd, J = 8, 4, 1H), 8.60(s, 1H), 8.90 fluoropicolinamide (bs, 2H), 10.24 (s, 1H)3-amino-N-(5-((1-amino-3- 1H NMR (400 MHz, DMSO-d6) δ: 3.11 (dd, J = 12,8, 1H), 3.22 458(M + 1) chloropropan-2-yl)oxy)isothiazol- (dd, J = 10,4, 1H), 3.77 (d, J = 8, 2H), 4.20-4.30 (m, 1H), 7.20-7.304-yl)-6-(2,6-difluorophenyl)-5- (m, 2H), 7.30 (bs, 2H), 7.40 (t, J = 8,2H), 7.45-7.75 (m, 1H), 7.99 fluoropicolinamide (bs, 2H), 8.55 (dd, J =8, 4, 1H), 9.20 (s, 1H), 10.05 (s, 1H) 3-amino-N-(5-(3-amino-2- 1H NMR(400 MHz, DMSO-d6) δ: 2.20-2.60 (m, 2H), 2.90-3.00 472(M + 1)(chloromethyl)propoxy)isothiazol- (m, 1H), 3.65 (s, 1H), 3.79 (d, J = 8,2H), 4.20-4.38 (m, 2H), 7.20- 4-yl)-6-(2,6-difluorophenyl)-5- 7.30 (m,2H), 7.30 (bs, 2H), 7.39 (t, J = 8, 2H), 7.45-7.75 (m, 1H),fluoropicolinamide 8.12 (bs, 2H), 8.45 (dd, J = 8, 4, 1H), 8.90 (s, 1H),9.90 (s, 1H) 3-amino-6-(2,6-difluorophenyl)-5- 1H NMR (400 MHz, DMSO-d6)δ: 1.40-1.50 (m, 1H), 1.66- 464(M + 1) fluoro-N-(5-(piperidin-3- 1.80(m, 1H), 2.03-2.08 (m, 1H), 2.20-2.28 (m, 1H), 2.54-2.60ylmethoxy)isothiazol-4- (m, 1H), 2.70-2.76 (m, 2H), 3.10-3.50 (m, 2H),4.20-4.40 (m, yl)picolinamide 2H), 7.20-7.30 (m, 2H), 7.30-7.36 (m, 2H),7.50-7.62 (m, 1H), 8.40 (dd, J = 8, 4, 1H), 8.88 (s, 1H), 9.03 (bs, 2H),10.35 (s, 1H) 3-amino-N-(5-(4- 1H NMR (400 MHz, DMSO-d6) δ: 1.50-1.55(m, 2H), 1.75-1.78 438(M + 1) aminobutoxy)isothiazol-4-yl)-6- (m, 2H),2.80-2.84 (m, 2H), 4.25 (t, J = 6, 2H), 7.21-7.31 (m, 2H),(2,6-difluorophenyl)-5- 7.34-7.36 (m, 3H), 7.50-7.60 (m, 1H), 7.90 (bs,2H), 8.44 (dd, fluoropicolinamide J = 8, 4, 1H), 7.75 (s, 1H), 10.25 (s,1H) 3-amino-N-(5-((3- 1H NMR (400 MHz, DMSO-d6) δ: 1.10-1.40 (m, 5H),2.60-2.80 464(M + 1) aminocyclohexyl)oxy)isothiazol-4- (m, 3H),3.05-3.50 (m, 1H), 3.95-4.05 (H), 7.20-7.30 (m, 2H),yl)-6-(2,6-difluorophenyl)-5- 7.35-7.37 (m, 3H), 7.50-7.62 (m, 1H), 7.91(bs, 3H), 8.42 (dd, fluoropicolinamide J = 8, 4, 1H), 8.80-8.90 (m, 1H),10.49 (s, 1H) N-(5-(4-aminobutoxy)isothiazol-4- 1H NMR (400 MHz,DMSO-d6) δ: 1.45-1.52 (m, 2H), 1.70-1.80 405(M + 1) yl)-6-(2,6- (m, 2H),2.80-2.84 (m, 2H), 4.20 (t, J = 6, 2H), 7.31-7.35 (m, 3H),difluorophenyl)picolinamide 7.59-7.66 (m, 1H), 7.91-7.93 (m, 1H),8.18-8.26 (m, 1H), 8.70 (bs, 2H), 9.01 (s, 1H), 10.11 (s, 1H)N-(5-(azetidin-3-yloxy)isothiazol-4- 1H NMR (400 MHz, DMSO-d6) δ:3.96-4.00 (m, 2H), 4.50-4.55 389(M + 1) yl)-6-(2,6- (m, 2H), 5.38 (bs,1H), 7.31-7.35 (m, 3H), 7.59-7.66 (m, 1H), difluorophenyl)picolinamide7.91-7.92 (m, 1H), 8.20-8.26 (m, 1H), 8.59 (bs, 2H), 8.99 (s, 1H), 10.29(s, 1H) (S)-6-(2,6-difluorophenyl)-N-(5- 1H NMR (400 MHz, DMSO-d6) δ:1.78-1.90 (m, 1H), 2.05-2.15 403(M + 1)(pyrrolidin-3-yloxy)isothiazol-4- (m, 1H), 2.68-2.75 (m, 1H), 2.90-3.00(m, 2H), 3.05-3.15 (m, yl)picolinamide 1H), 5.00-5.15 (m, 1H), 7.29-7.35(m, 3H), 7.59-7.66 (m, 1H), 7.90-7.95 (m, 1H), 8.20 (d, J = 8, 1H), 8.75(bs, 2H), 9.01, 10.36 (s, 1H) 6-(2,6-difluorophenyl)-N-(5- 1H NMR (400MHz, DMSO-d6) δ: 1.95-2.03 (m, 2H), 2.14-2.20 417(M + 1)(piperidin-4-yloxy)isothiazol-4- (m, 2H), 3.11-3.16 (m, 2H), 3.23-3.28(m, 2H), 4.58-4.63(m, 1H), yl)picolinamide 7.31-7.35 (m, 2H), 7.59-7.66(m, 1H), 7.91-7.93 (m, 1H), 8.18- 8.26 (m, 1H), 8.59 (bs, 2H), 10.09 (s,1H) N-(5-(azepan-4-yloxy)isothiazol-4- 1H NMR (400 MHz, DMSO-d6) δ: 1.60(bs, 1H), 1.93 (d, J = 8, 431(M + 1) yl)-6-(2,6- 1H), 2.10-2.15 (m, 3H),2.80-3.14 (m, 4H), 3.57 (bs, 1H), 4.49 difluorophenyl)picolinamide (bs,1H), 7.30-7.35 (m, 3H), 7.60-7.65 (m, 1H), 7.90-7.92 (m, 1H), 8.20 (d, J= 8, 1H), 8.80 (bs, 2H), 8.89 (s, 1H), 9.98 (s, 1H) N-(5-(azetidin-3- ¹HNMR (400 MHz, DMSO-d6) δ: 1.98-2.00 (m, 1H), 3.65-4.30 403(M + 1)ylmethoxy)isothiazol-4-yl)-6-(2,6- (m, 4H), 4.58 (d, J = 6, 2H),7.30-7.35 (m, 3H), 7.59-7.65 (m, 1H), difluorophenyl)picolinamide7.91-7.93 (m, 1H), 8.20-8.25 (m, 1H), 8.60 (bs, 2H), 9.10, 10.00 (s, 1H)6-(2,6-difluorophenyl)-N-(5- ¹H NMR (400 MHz, DMSO-d6) δ: 1.70-1.75 (m,1H), 2.10-2.15 417(M + 1) (pyrrolidin-3-ylmethoxy)isothiazol- (m, 1H),2.70-2.80 (m, 1H), 2.85-3.00 (m, 2H), 3.00-3.05 (m, 4-yl)picolinamide1H), 3.15-3.20 (m, 1H), 4.45 (d, J = 6, 2H), 7.30-7.35 (m, 3H),7.60-7.66 (m, 1H), 7.90-7.92 (m, 1H), 8.20-8.25 (m, 1H), 8.60 (bs, 2H),9.05 (s, 1H), 10.09 (s, 1H) 6-(2,6-difluorophenyl)-N-(5- ¹H NMR (400MHz, DMSO-d6) δ: 1.45-1.60 (m, 1H), 1.80 (d, 430(M + 1)(piperidin-4-ylmethoxy)isothiazol- J = 14, 2H), 1.90-2.10 (m, 2H),2.65-2.70 (m, 2H), 3.10 (d, J = 10, 4-yl)picolinamide 2H), 4.26 (d, J =6, 2H), 7.31-7.35 (m, 3H), 7.60-7.65 (m, 1H), 7.91-7.93 (m, 1H), 8.20(d, J = 8, 1H), 8.59 (bs, 2H), 8.95 (s, 1H), 10.22 (s, 1H)N-(5-((1-amino-3-chloropropan-2- ¹H NMR (400 MHz, DMSO-d6) δ: 3.10 (dd,J = 12, 8, 1H), 3.25 425(M + 1) yl)oxy)isothiazol-4-yl)-6-(2,6- (dd, J =10, 4, 1H), 3.80 (d, J = 8, 2H), 4.15-4.30 (m, 1H), 7.30-7.35difluorophenyl)picolinamide (m, 3H), 7.59-7.66 (m, 1H), 7.90-7.93 (m,1H), 8.20-8.26 (m, 1H), 8.40 (bs, 2H), 9.00 (s, 1H), 10.47 (s, 1H)N-(5-(3-amino-2- ¹H NMR (400 MHz, DMSO-d6) δ: 2.20-2.70 (m, 2H),2.95-3.05 439(M + 1) (chloromethyl)propoxy)isothiazol-4- (m, 1H), 3.62(s, 1H), 3.82 (d, J = 8, 2H), 4.20-4.40 (m, 2H), 7.31- yl)-6-(2,6- 7.35(m, 3H), 7.60-7.665(m, 1H), 7.91-7.95 (m, 1H), 8.20-8.25difluorophenyl)picolinamide (m, 1H), 8.40 (bs, 2H), 10.40 (s, 1H)3-amino-N-(5-(4- ¹H NMR (400 MHz, DMSO-d6) δ: 1.50-1.52 (m, 2H),1.70-1.80 420(M + 1) aminobutoxy)isothiazol-4-yl)-6- (m, 2H), 2.80-2.82(m, 2H), 4.21 (t, J = 6, 2H), 7.010-7.40 (m,(2,6-difluorophenyl)picolinamide 5H), 7.59 (bs, 2H), 8.33 (bs, 1H), 8.86(s, 1H), 9.90 (bs, 1H) 3-amino-N-(5-(azetidin-3- 1H NMR (400 MHz, CD₃OD)δ: 4.29 (d, J = 11, 2H), 4.49-4.59 404(M + 1)yloxy)isothiazol-4-yl)-6-(2,6- (m, 2H), 5.22 (bs, 1H), 7.10 (t, J = 7,2H), 7.32 (d, J = 9, 1H), 7.40- difluorophenyl)picolinamide 7.53 (m,2H), 8.80 (s, 1H) (S)-3-amino-6-(2,6-difluorophenyl)- 1H NMR (400 MHz,DMSO-d6) δ: 1.80-1.92 (m, 1H), 2.05-2.15 418(M + 1)N-(5-(pyrrolidin-3-yloxy)isothiazol- (m, 1H), 2.71-2.84 (m, 1H),2.90-3.00 (m, 2H), 3.04-3.15 (m, 4-yl)picolinamide 1H), 5.00-5.20 (m,1H), 7.10-.40 (m, 5H), 7.52 (bs, 2H), 8.35 (bs, 1H), 9.01 (s, 1H), 9.80(bs, 1H) (R)-3-amino-6-(2,6-difluorophenyl)- 1H NMR (400 MHz, DMSO-d6)δ: 1.79-1.90 (m, 1H), 2.05-2.15 418(M + 1)N-(5-(pyrrolidin-3-yloxy)isothiazol- (m, 1H), 2.70-2.85 (m, 1H),2.90-3.00 (m, 2H), 3.04-3.15 (m, 4-yl)picolinamide 1H), 5.00-5.20 (m,1H), 7.10-.40 (m, 5H), 7.52 (bs, 2H), 8.35 (bs, 1H), 9.01 (s, 1H), 9.80(bs, 1H) 3-amino-6-(2,6-difluorophenyl)-N- 1HNMR (400 MHz, DMSO-d6): δ:1.44-1.46 (m, 2H), 1.85-1.87 432(M + 1)(5-(piperidin-4-yloxy)isothiazol-4- (m, 2H), 2.35-2.37 (m, 2H),2.80-2.83 (m, 2H), 4.67-4.68 (m, yl)picolinamide 1H), 7.05-7.40 (m, 5H),7.55 (bs, 2H), 8.33 (bs, 1H), 8.88 (s, 1H), 9.07 (s, 1H), 10.01 (bs, 1H)3-amino-N-(5-(azepan-4- 1H NMR (400 MHz, DMSO-d6) δ: 1.769 (d, J = 6,1H), 1.98 (d, 446(M + 1) yloxy)isothiazol-4-yl)-6-(2,6- J = 7, 1H),2.03-2.30 (m, 4H), 3.02 (m, 4H), 3.10-3.19 (m, 1H),difluorophenyl)picolinamide 4.52 (bs, 1H), 7.05-7.38 (m, 5H), 7.53 (bs,2H), 8.34 (bs, 1H), 8.85 (s, 1H), 8.97 (s, 1H), 9.95 (bs, 1H)3-amino-N-(5-(azetidin-3- ¹H NMR (400 MHz, DMSO-d6) δ: 1.96 (bs, 1H),3.70-4.30 (m, 418(M + 1) ylmethoxy)isothiazol-4-yl)-6-(2,6- 4H), 4.59(d, J = 6, 2H), 7.09-7.42 (m, 5H), 7.60 (bs, 2H), 8.35 (bs,difluorophenyl)picolinamide 1H), 8.76 (s, 1H), 9.02 (s, 1H), 10.10 (bs,1H) 3-amino-6-(2,6-difluorophenyl)-N- ¹H NMR (400 MHz, DMSO-d6) δ:1.72-1.74 (m, 1H), 2.10-2.15 432(M + 1) (5-(pyrrolidin-3- (m, 1H),2.75-2.90 (m, 1H), 2.85-3.00 (m, 2H), 3.00-3.05 (m,ylmethoxy)isothiazol-4- 1H), 3.15-3.20 (m, 1H), 4.47 (d, J = 8, 2H),7.00-7.35 (m, 5H), yl)picolinamide 8.00 (bs, 2H), 8.42 (bs, 1H), 8.81(s, 1H), 8.97 (s, 1H), 10.02 (bs, 1H) 3-amino-6-(2,6-difluorophenyl)-N-1H NMR (400 MHz, DMSO-d6) δ: 1.34 (bs, 2H), 1.78 (bs, 2H), 446(M + 1)(5-(piperidin-4- 2.69 (bs, 3H), 3.12 (bs, 3H), 4.11 (bs, 1H), 7.07-7.40(m, 5H), ylmethoxy)isothiazol-4- 7.53 (bs, 2H), 8.33 (bs, 1H), 8.86 (s,1H), 9.01, 9.83 (bs, 1H) yl)picolinamide 3-amino-N-(5-((1-amino-3- ¹HNMR (400 MHz, DMSO-d6) δ: 3.12 (dd, J = 12, 8, 1H), 3.20 440(M + 1)chloropropan-2-yl)oxy)isothiazol-4- (dd, J = 10, 4, 1H), 3.77 (d, J = 8,2H), 4.16-4.25 (m, 1H), 7.10-7.40 yl)-6-(2,6- (m, 5H), 7.66 (bs, 3H),8.30 (bs, 1H), 8.79 (s, 1H), 9.07, 9.91 (bs, difluorophenyl)picolinamide1H) 3-amino-N-(5-(3-amino-2- ¹H NMR (400 MHz, DMSO-d6) δ: 2.20-2.60 (m,2H), 3.00-3.05 454(M + 1) (chloromethyl)propoxy)isothiazol-4- (m, 1H),3.60 (s, 1H), 3.80 (d, J = 8, 2H), 4.20-4.40 (m, 2H), 7.10- yl)-6-(2,6-7.40 (m, 5H), 7.56 (bs, 3H), 8.30 (bs, 1H), 8.85 (s, 1H), 9.08 (s,difluorophenyl)picolinamide 1H), 10.02 (bs, 1H)3-amino-6-(2,6-difluorophenyl)-N- ¹H NMR (400 MHz, DMSO-d6) δ: 1.90 (s,2H), 3.55 (s, 2H), 407(M + 1) (5-(3-hydroxypropoxy)isothiazol-4- 3.27(s, 2H), 4.63 (s, 1H), 7.14 (s, 2H), 7.22 (t, J = 8, 2H), 7.38 (d,yl)picolinamide J = 5, 1H), 7.50-7.60 (m, 2H), 8.82 (s, 1H), 9.83 (s,1H)

Example 60

The biochemical assays used to test the activities of the compounds ofthe present invention and their results.

In the present invention, the PIM activities of the compounds weretested by BioDuro (Building E, No. 29 Life Science Park Road, ChangpingDistrict, Beijing, 102206, P.R. China). The method used for testing isPIM Kinase Activity Assay-IMAP Fluorescence Polarization Assay

PIM Kinase Activity Assay-IMAP Fluorescence Polarization Assay

1. Principle

PIM Is a serine/threonine protein kinase, they can phosphorylate 5-FAMlabeled small peptide substrates. Fluorescence polarization is less fornon-phosphorylated substrates since that can not bind to the binder(metal binding nanoparticles). On the other hand, fluorescencepolarization is more for phosphorylated substrates since that can bindto the binder. The level of 5-FAM labeled small peptide substratesphosphorylation reflects the activities of PIM kinase. By measuringtheir ability of inhibiting PIM kinase of the compounds of the presentinvention, their activities of inhibiting PIM kinases can be determined.

2. Instrument

EnVision (PerkinElmer, Waltham, Mass.)

3. Reagents and 384 well plates

PIM1 (Millipore Cat. #14-573) (Millipore Corporation, Billerica, Mass.)

PIM2 (Millipore Cat.#14-607) (Millipore Corporation, Billerica, Mass.)

5-FAM labeled peptide (5-FAM-RSRHSSYPAGT, AnaSpec Cat.#63801) (AnaSpecInc., Fremont, Calif.)

IMAP FP Screening Express kit (IMAP FP Screening kit) (Molecular DevicesCat.# R8127) (Molecular Devices, Sunnyvale, Calif.)

IMAP Progressive binding reagent

IMAP Progressive binding buffer A (5X)

IMAP Progressive binding buffer B (5X)

384-well black plate (Corning Cat.#3573) (Corning, Midland Mich.)

4. Assay Buffer

Tris-HCl (pH 7.2): 10 mM

MgCl₂:10 mM

Triton X-100: 0.01%

DTT: 2 mM

5. Procedure

a) 10 mM compound stock solution is diluted to appropriate concentrationwith 100% DMSO, then diluted 10 fold to targeted concentration with testbutter to keep DMSO concentration at 10%b) Assay volume 10 ul:1 ul of compound solution and 4 ul of enzyme (PIM-1 final concentration0.025 nM, PIM-2 concentration 3 nM) is incubated at 23° C. for 15 min,2.5 ul ATP (for PIM-1 and PIM-2, the final ATP concentrations are 30 uMand 5 uM respectively) 2.5 ul 5-FAM labeled peptide (final concentration100 nM) was added to start the reaction. The reaction is run at 23° C.for 60 min. DMSO is used in place of compound stock solution as maximumreference and assay buffer is used in place of enzyme as minimumreference.c) add 30 ul IMAP binding reagent (containing 75% IMAP Buffer A, 25%IMAP Buffer B, 1/600 dilution of beads) to stop the reaction, incubatedat room temperature for 60 mind) Measure fluorescence polarization, excitation wavelength: 485 nm,emission wavelength 530 nm.6. Data processIC₅₀ values were calculated using Graphpad Prism®.PIM kinase assays showed that all 59 compounds in Example 1 through 59can significantly inhibit the PIM-1, PIM-2 and PIM-3 activities. TheIC₅₀ of these compounds range from 0.1 nM to 50 nM.

We claim:
 1. A compound having a structure of Formula II:

wherein R₁ is a hydrogen, —NHR₄, a halogen, a hydroxyl, an alkyl, acyano, or a nitro; R₂ and R₃ are each independently selected from ahydrogen, —NHR₅, a halogen, a hydroxyl, a substituted or unsubstitutedalkyl, an alkenyl, an alkynyl, an alkoxyl, a cycloalkyl, an amino, acyano, and a nitro; R₄ is a hydrogen, —C(═O)—R₅, a substituted orunsubstituted alkyl, a cycloalkyl, a heterocyclyl, an aryl, or aheteroaryl; R₅ is a substituted or unsubstituted alkyl, alkenyl,alkynyl, alkoxyl, cycloalkyl, amino, or substituted amino; R₆ is asubstituted or unsubstituted aryl, heteroaryl, cycloalkyl, wherein eachsubstituted R₆ group is substituted with up to four substituents that isa halogen, a cyano, an amino, a C₁₋₄ alkyl, a C₃₋₆ cycloalkyl, analkoxyl, a nitro, a carboxy, a carbonyl, a carboalkoxy, or anaminocarboxy; R₂₂ is an optionally substituted C₁-C₈ hydrocarbon groupor a group having a formula:

wherein each of R₂₃, R₂₄, R₂₅ is independently selected from a H, ahalogen, OR₁₅, NR₁₆R₁₇, C(═O)NR₁₈R₁₉, or an optionally substituted C₁-C₈hydrocarbon group; or R₂₃, R₂₄ and R₂₅, together with atoms to whichthey are attached, are joined together to form a chain so that the ringto which they are attached is a substituted C₆-C₁₄ membered spiral ring,a bicyclic ring, or a fused ring group; G₁ is CH or N; G₂ is NR₂₈,CHR₂₉, or O; B1 and B2 each independently represents 0, 1, 2, or 3; B3is 0, 1, or 2; B4 is 0 or 1; each of R₁₆, R₁₇, R₁₈, R₁₉, R₂₆ and R₂₇ isindependently selected from a H or an optionally substituted C₁-C₈hydrocarbon group; R₂₈ is H, an optionally substituted hydrocarbongroup, an optionally substituted cyclic hydrocarbon group, an optionallysubstituted heterocyclic hydrocarbon group, C(═O)R₃₀, C(═O)OR₃₀, orC(═O)NHR₃₀; R₂₉ is OH, NHR₃₀, C(═O)OR₃₀, or C(═O)NHR₃₀; and R₃₀ is H oran optionally substituted C₁-C₈ hydrocarbon group.
 2. The compoundaccording to claim 1, wherein R₂₂ is a substituted or unsubstitutedcyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidyl,pyrrolidinyl, piperidinyl, azepanyl, oxetyl, tetrahydrofuryl, ortetrahydropyranyl group; R₂₂ group is substituted with up to threesubstitutents that is an amino, a hydroxy, a methyl, an ethyl, or amethoxy; R₁ is a hydrogen, an amino, or a fluoro; R₂ and R₃ are eachindependently selected from a hydrogen, a halogen, or a methyl; and R₆is a substituted or unsubstituted phenyl, wherein the substituted phenylgroup is substituted with up to three substituents that is a hydrogen, acyano, a nitro, a halogen, a hydroxyl, an amino, an alkoxy, asubstituted amino, an alkyl, or a cycloalkyl.
 3. The compound accordingto claim 2, wherein R₂₂ is a substituted or unsubstituted cyclohexyl,cycloheptyl, pyrrolidinyl, piperidinyl, or azepany group; when R₂₂ is asubstituted group, it is substituted with up to three substitutents thatis an amino, a hydroxy, or a methyl; R₁ is a hydrogen, an amino, or afluoro; R₂ and R₃ are each independently selected from a hydrogen, ahalogen, and a methyl; and R₆ is a substituted or unsubstituted phenyl,and the substituted phenyl group is substituted with up to threesubstituents that is a hydrogen, a cyano, a nitro group, a halogen, or ahydroxyl.
 4. The compound according to claim 1, wherein R₂₂ is asubstituted or unsubstituted cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, cycloheptylmethyl, azetidylmethyl, pyrrolidinylmethyl,piperidinylmethyl, azepanylmethyl, oxetylmethyl, tetrahydrofurylmethyl,or tetrahydropyranylmethyl group; R₂₂ group is substituted with up tothree substitutents that is an amino, a hydroxy, a methyl, an ethyl, ora methoxy; R₁ is a hydrogen, an amino, or a fluoro; R₂ and R₃ are eachindependently selected from a hydrogen, a halogen, or a methyl; and R₆is a substituted or unsubstituted phenyl, and the substituted phenyl issubstituted with up to three substituents that is a hydrogen, a cyano, anitro, a halogen, a hydroxyl, an amino, an alkoxy, a substituted amino,an alkyl, or a cycloalkyl.
 5. The compound according to claim 4, whereinR₂₂ is a substituted or unsubstituted cyclohexylmethyl,pyrrolidinylmethyl, piperidinylmethyl, or azepanylmethyl group, thesubstituted R₂₂ group is substituted with up to three substitutents thatis an amino, a hydroxy, or a methyl; R₁ is a hydrogen, an amino, or afluoro; R₂ and R₃ are each independently selected from a hydrogen, ahalogen, or a methyl; and R₆ is a substituted or unsubstituted phenyl,and the substituted phenyl is substituted with up to three substituentsthat is a hydrogen, a cyano, or a halogen.
 6. The compound according toclaim 4, wherein R₂₂ is a substituted C₂-C₅ alkyl, the substituted R₂₂group is substituted at any position on substituent with up to foursubstitutents that is an amino, an alkylamino, a hydroxy, a halogen, amethyl, an ethyl, a halogenated methyl, or a helogenated ethyl group; R₁is a hydrogen, an amino, or a fluoro; R₂ is a hydrogen; R₃ is a halogen;and R₆ is a substituted or unsubstituted phenyl, and the substitutedphenyl is substituted with up to three substituents that is a hydrogen,a methyl, or a halogen.
 7. The compound according to claim 3, wherein R₁is a hydrogen or an amino; R₂ is hydrogen; R₃ is a halogen; R₆ is asubstituted or unsubstituted phenyl, and the substituted phenyl issubstituted with up to three substituents that is a hydrogen or ahalogen.
 8. The compound according to claim 5, wherein R₁ is a hydrogenor an amino; R₂ is hydrogen; R₃ is a halogen; R₆ is a substituted orunsubstituted phenyl, and the substituted phenyl is substituted with upto three substituents that is a hydrogen or a halogen.
 9. The Pim kinaseinhibitor according to claim 1, wherein the Pim kinase inhibitor is thecompound as represented by Formular II or a stereoisomer, tautomer, or apharmaceutically acceptable salt thereof.
 10. The Pim kinase inhibitorsaccording to claim 1, wherein the compound is6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-4-ylmethoxy)isothiazol-4-yl)picolinamide,N-(5-(azetidin-3-ylmethoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-4-yloxy)isothiazol-4-yl)picolinamide,6-(2,6-difluorophenyl)-5-fluoro-N-(5-(pyrrolidin-3-yloxy)isothiazol-4-yl)picolinamide,6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-3-yloxy)isothiazol-4-yl)picolinamide,N-(5-(azepan-4-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-3-ylmethoxy)isothiazol-4-yl)picolinamide,6-(2,6-difluorophenyl)-5-fluoro-N-(5-(pyrrolidin-3-ylmethoxy)isothiazol-4-yl)picolinamide,N-(5-(azetidin-3-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,N-(5-(((1r,4r)-4-aminocyclohexyl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,N-(5-((3-aminocyclohexyl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,N-(5-(3-aminopropoxyl)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,6-(2,6-difluorophenyl)-5-fluoro-N-(5-(3-(methylamino)propoxy)isothiazol-4-yl)picolinamide,6-(2,6-difluorophenyl)-N-(5-(3-(dimethylamino)propoxy)isothiazol-4-yl)-5-fluoropicolinamide,N-(5-(4-aminobutoxyl)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,6-(2,6-difluorophenyl)-5-fluoro-N-(5-(4-(methylamino)butoxy)isothiazol-4-yl)picolinamide,6-(2,6-difluorophenyl)-5-fluoro-N-(5-(3-hydroxypropoxyl)isothiazol-4-yl)picolinamide,6-(2,6-difluorophenyl)-5-fluoro-N-(5-(3-hydroxybutoxyl)isothiazol-4-yl)picolinamide,6-(2,6-difluorophenyl)-5-fluoro-N-(5-(4-hydroxybutoxyl)isothiazol-4-yl)picolinamide,6-(2,6-difluorophenyl)-5-fluoro-N-(5-((4-hydroxy-4-methylpentyl)oxy)isothiazol-4-yl)picolinamide,6-(2,6-difluorophenyl)-N-(5-(3,4-dihydroxybutoxyl)isothiazol-4-yl)-5-fluoropicolinamide,6-(2,6-difluorophenyl)-5-fluoro-N-(5-((tetrahydro-2H-pyran-4-yl)methoxy)isothiazol-4-yl)picolinamide,3-amino-6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-4-ylmethoxy)isothiazol-4-yl)picolinamide,3-amino-6-(2,6-difluorophenyl)-5-fluoro-N-(5-(pyrrolidin-3-yloxy)isothiazol-4-yl)picolinamide,3-amino-6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-4-yloxy)isothiazol-4-yl)picolinamide,3-amino-N-(5-(azepan-4-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,3-amino-N-(5-(((1r,4r)-4-aminocyclohexyl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,3-amino-6-(2,6-difluorophenyl)-5-fluoro-N-(5-(pyrrolidin-3-ylmethoxy)isothiazol-4-yl)picolinamide,N-(5-((1-amino-3-chloropropan-2-yl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,N-(5-(3-amino-2-(chloromethyl)propoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,3-amino-N-(5-(azetidin-3-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,3-amino-N-(5-(azetidin-3-ylmethoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,3-amino-N-(5-((1-amino-3-chloropropan-2-yl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,3-amino-N-(5-(3-amino-2-(chloromethyl)propoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,3-amino-6-(2,6-difluorophenyl)-5-fluoro-N-(5-(piperidin-3-ylmethoxy)isothiazol-4-yl)picolinamide,3-amino-N-(5-(4-aminobutoxyl)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,3-amino-N-(5-((3-aminocyclohexyl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide,N-(5-(4-aminobutoxyl)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide,N-(5-(azetidin-3-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide,(S)-6-(2,6-difluorophenyl)-N-(5-(pyrrolidin-3-yloxy)isothiazol-4-yl)picolinamide,6-(2,6-difluorophenyl)-N-(5-(piperidin-4-yloxy)isothiazol-4-yl)picolinamide,N-(5-(azepan-4-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide,N-(5-(azetidin-3-ylmethoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide,6-(2,6-difluorophenyl)-N-(5-(pyrrolidin-3-ylmethoxy)isothiazol-4-yl)picolinamide,6-(2,6-difluorophenyl)-N-(5-(piperidin-4-ylmethoxy)isothiazol-4-yl)picolinamide,N-(5-((1-amino-3-chloropropan-2-yl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide,N-(5-(3-amino-2-(chloromethyl)propoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide,3-amino-N-(5-(4-aminobutoxyl)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide,3-amino-N-(5-(azetidin-3-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide,(S)-3-amino-6-(2,6-difluorophenyl)-N-(5-(pyrrolidin-3-yloxy)isothiazol-4-yl)picolinamide,(R)-3-amino-6-(2,6-difluorophenyl)-N-(5-(pyrrolidin-3-yloxy)isothiazol-4-yl)picolinamide,3-amino-6-(2,6-difluorophenyl)-N-(5-(piperidin-4-yloxy)isothiazol-4-yl)picolinamide,3-amino-N-(5-(azepan-4-yloxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide,3-amino-N-(5-(azetidin-3-ylmethoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide,3-amino-6-(2,6-difluorophenyl)-N-(5-(pyrrolidin-3-ylmethoxy)isothiazol-4-yl)picolinamide,3-amino-6-(2,6-difluorophenyl)-N-(5-(piperidin-4-ylmethoxy)isothiazol-4-yl)picolinamide,3-amino-N-(5-((1-amino-3-chloropropan-2-yl)oxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide,3-amino-N-(5-(3-amino-2-(chloromethyl)propoxy)isothiazol-4-yl)-6-(2,6-difluorophenyl)picolinamide,or3-amino-6-(2,6-difluorophenyl)-N-(5-(3-hydroxypropoxy)isothiazol-4-yl)picolinamide.11. A method for using the compound of claim 1, comprising administeringto an object in need of a treatment a therapeutically effective amountof the compound as described in claim 1, wherein the treatment is fortreating or preventing human chronic lymphocytic leukemia, acutelymphoblastic leukemia, acute myeloid leukemia, chronic myelogenousleukemia, non-Hodgkin's lymphoma, multiple myeloma, pancreatic cancers,prostate cancers, liver cancers, gastric cancer, bladder cancer, multidrug resistance, and inflammatory bowel disease.
 12. The method forusing the Pim kinase inhibitor of claim 9, comprising administering toan object in need of a treatment a therapeutically effective amount ofthe Pim kinase inhibitor as described in claim 9, wherein the treatmentis for treating or preventing human chronic lymphocytic leukemia, acutelymphoblastic leukemia, acute myeloid leukemia, chronic myelogenousleukemia, non-Hodgkin's lymphoma, multiple myeloma, pancreatic cancers,prostate cancers, liver cancers, gastric cancer, bladder cancer, multidrug resistance, and inflammatory bowel disease.
 13. The method forusing the Pim kinase inhibitor of claim 10, comprising administering toan object in need of a treatment a therapeutically effective amount ofthe Pim kinase inhibitor as described in claim 10, wherein the treatmentis for treating or preventing human chronic lymphocytic leukemia, acutelymphoblastic leukemia, acute myeloid leukemia, chronic myelogenousleukemia, non-Hodgkin's lymphoma, multiple myeloma, pancreatic cancers,prostate cancers, liver cancers, gastric cancer, bladder cancer, multidrug resistance, and inflammatory bowel disease.
 14. A pharmaceuticalcomposition according to claim 1, comprising the compound of claim 1 asan active pharmaceutical ingredient, and pharmaceutically acceptablecarriers and adjuvants.
 15. The pharmaceutical composition according toclaim 9, comprising the Pim kinase inhibitor of claim 9 as an activepharmaceutical ingredient, and pharmaceutically acceptable carriers andadjuvants.
 16. The pharmaceutical composition according to claim 10,comprising the Pim kinase inhibitor of claim 10 as an activepharmaceutical ingredient, and pharmaceutically acceptable carriers andadjuvants.